PHARMACOLOGICALLY ACTIVE PEPTIDE CONJUGATES HAVING A REDUCED TENDENCY TOWARDS ENZYMATIC HYDROLYSIS

Abstract: The invention is directed to a pharmacologically active peptide conjugate having a reduced tendency towards enzymatic cleavage comprising a pharmacologically active peptide sequence (X) and a stabilising peptide sequence (Z) of 4-20 amino acid residues covalently bound to X.

Description: PHARMACOLOGICALLY ACTIVE PEPTIDE CONJUGATES HAVING A REDUCED TENDENCY TOWARDS ENZYMATIC HYDROLYSIS FIELD OF THE INVENTION The present invention relates to pharmacologically active peptide conjugates having a reduced tendency towards enzymatic cleavage. BACKGROUND OF THE INVENTION There exist a large number of pharmacologically active peptides, e.g., naturally occurring in man or in animals, or synthetic analogues of such peptides. An illustrative example of such a peptide is the analgetically active peptide enkephalin that has given rise to a vast number of synthetic analogues. However, due to precisely their peptic nature, the routes of administration thereof have been rather limited. Thus, peptides are rapidly and very effectively degraded by enzymes, generally with half-lives in the range of minutes. Proteases and other proteolytic enzymes are ubiquitous, particularly in the gastro-intestinal tract, and therefore peptides are usually susceptible to degradation in multiple sites upon oral administration, and to some extent in the blood, the liver, the kidney, and the vascular endothelia. Furthermore, a given peptide is usually susceptible to degradation at more than one linkage within the backbone; each locus of hydrolysis is mediated by a certain protease. Even if such obstacles are overcome, for neuropeptides in particular, difficulties have been encountered in their transport across the blood-brain barrier. There has been a number of attempts to protect peptides against premature degradation (reviewed in Prokai, 1997, Exp. Opin. Ther. Patent 7:233-245, Tamai et al., 1996, Adv. Drug Delivery Rev. 19:401-424 and Zhou et al., 1991, Int. J. Pharm. 75:97-115). One approach includes osmotically altering the blood-brain barrier by infusion of hypertonic solutions of mannitol, arabinose, lactamide, saline, urea, glycerol and radiographic contrast agents. However, there could be toxic side effects. Another approach involves the use of protease inhibitors (reviewed in Zhou et al., 1991, Int. J. Pharm. 75:97-1 15). This approach has yielded mixed results. A third approach has involved the use of absorption enhancers in peptide formulations (reviewed in Zhou et al., 1991, Int. J. Pharm. 75:97-115). Examples include fatty acids and bile salts. However, varying results have been obtained regarding efficacies and the value of a particular enhancer is dependent on the route of administration used. Another approach for enhancing the absorption of peptides involves chemically modifying the peptide by, for example, attaching a liphophilic moiety. It has also been found that attaching a pyroglutamyl residue at the N-terminal end can render a compound relatively resistant to hydrolysis. Tamai et al., 1996, Adv. Drug Delivery Rev. 19:401-404, discloses that E2078, a dynorphin analog was chemically modified to make it more stable to enzyme degradation by adding an N-methyl group at the amino-terminus of Arg and replacing D- Leu with L-Leu and adding ethylamine at the carboxy -terminal. A different approach involves the formation of chimeric peptides. This approach involves coupling the peptide that is not normally transported through the blood-brain barrier to peptide or protein 'vectors' that undergo receptor-mediated or adsorptive-mediated transcytosis. WO 98/22577 discloses a method for increasing the resistance of a "core protein" to proteolytic degradation by linking or inserting a "stabilizing polypeptide" having the formula [(Gly a )X(Gly b )Y[(Gly c )Z]n. X, Y, and Z may be alanine, serine, valine, isoleucine, leucine, methionine, phenylalanine, proline, and threonine. U.S. Patent No. 5,545,719 discloses molecules comprising protein fragments homologous to an active region of protein fragments capable of stimulating nerve growth (neuronotrophic proteins such as epidermal growth factor, tubulin, nerve growth factor, laminin, fibronectin, ncam and ependymin) no greater than 80 amino acids long connected to a secondary molecule which can be a second protein fragment derived from the original protein, from another protein or from a non-proteinaceous moiety. This secondary molecule facilitates the transport of the peptide across the blood-brain barrier. It is stated in column 3, lines 3-7, "Upon entering the central nervous system, prodrug can remain intact or the chemical linkage between the carrier and the protein fragment may be hydrolyzed thereby separating the carrier from the fragment to release the nerve growth-stimulating fragment". A preferred method for facilitating the coupling of the secondary molecule to the protein fragment is via one or more basic amino acids, preferably a pair of Lys residues, an Arg residue, or Arg- Lys. Fawell et al., 1994, Proc. Natl. Acad. Sci. USA 91 : 664-668 discloses chemically crosslinking various Tat peptide fragments to β-galactosidase, RNAse A and domain III of pseudomonas exotoxin A. These included Tat-(37-72), Tat -(37-58) and Tat-(47-58). All of these peptides appeared to promote uptake of galactosidase, RNAse and domain III into cells. It was stated that this is the basic region of Tat. Conjugates containing poly (L-lysine) or poly (L-arginine) were not taken up by the cells. WO 97/24445 discloses fusion proteins of albumin and growth hormone or variants thereof. It is stated in the specification that variants of albumin should have the oncotic, ligand- binding and non-immunogenic properties of full length albumin and that variants of growth hormone should have its non-immunogenicity and ability to bind and activate the growth hormone receptor. WO98/28427 discloses an Fc-OB fusion protein. Fc is an immunoglobulin fragment and OB is leptin. It has been found that such conjugates are more stable than OB alone. The Fc fragment is 378 amino acids in length. The Fc fragment can be conjugated directly or via a linker to OB or an OB fragment. A further approach involves preparing peptide analogs with increased stability and/or activity by adding a peptide tail. Greene et al., J. Pharm. Exp. Therap. 277:1366-1375, discloses results of studies with various enkephalin analog prodrugs of [D-Pen 2 , D-Pen 5 ] enkephalin (DPDPE) and [D-Pen 2 , L-Cys 5 ] enkephalin (DPLCE), specifically DPLCE-Arg- Pro-Ala, DPDPE-Phe, DPLCE-Phe, DPDPE-Arg-Gly, DPLCE-Arg-Gly, DPDPE-Phe-Ala- NH-C 6 H ]3 , DPDPE-Phe-Ala-CONH 2 . The half lives of most of the analogs, except for DPDPE- Arg-Gly are less than the parent compounds. It is stated on page 1372, column 2 that "the ideal CNS-targeted prodrug would have a long half-life in the serum and a short half-life in the brain." U.S. Patent No. 4,724,229 discloses vasopressin antagonists which have a tripeptide side chain having three basic amino acids, such as arginine, lysine or ornithine which have potent antagonistic activity. U.S. Patent No. 4,542,124, discloses vasopressin antagonists which have a dipeptide side chain having two amino acids, one of which is basis which has potent vasopressin antagonistic activity. In the international patent application PCT/DK97/00376 (Bjarne Due Larsen and Arne Holm) prodrugs of pharmacologically active peptides are described, wherein the pharmacologically active peptide is coupled at its C-terminal to a peptide pre-sequence via a linker, the linker typically being an α-hydroxy carboxylic acid. These special peptide derivatives were found to have a prolonged half-life in the presence of proteolytic enzymes such as carboxypeptidase A, leucine aminopeptidase, pepsin A and α-chymotrypsin. In addition, PCT/DK97/00376 discloses (as reference compounds) four different peptides equipped with a peptide pre-sequence but without linker, namely DSIP-(Lys-Glu) 3 , DSIP- (Glu) , Leu-enkephalin-(Glu) and Leu-enkephalin-(Lys) . It is evident that there is a need for a peptide conjugate which contains a pharmacologically active peptide and a stabilising protein that is relatively simple to synthesize, retains its activity even without removing the stabilising peptide, is stable in plasma or serum and is relatively resistant to enzyme degradation. Therefore, it is an object of the invention to provide a peptide conjugate comprising a pharmacologically active peptide and stabilising peptide that is relatively resistant to enzyme degradation. SUMMARY OF THE INVENTION It has now surprisingly been found that by conjugating a pharmacologically active peptide, for example, at its C-terminal, at its N-terminal or at its C- and N-terminal, with a suitable stabilising peptide sequence, it is possible to render the resulting peptide conjugate significantly less susceptible to degradation by proteases compared to the corresponding free pharmacologically active peptide. Without being bound to any specific model for this effect, it is believed that the presence of the stabilising peptide sequence induces a degree of structuring, based on hydrogen bonds, of the pharmacologically active peptide, whereby the peptide conjugate is less susceptible to proteases in contrast to peptides in the random-coil conformation. As a result of the structuring, the peptide conjugate is much more difficult for a protease to degrade. Moreover, the resulting peptide conjugate is still pharmacologically active, i.e. the peptide conjugate possesses the ability to exert the pharmacological function of the free pharmacologically active peptide. Thus, in a first aspect the invention relates to a pharmacologically active peptide conjugate having a reduced tendency towards enzymatic cleavage, said peptide conjugate comprises: a pharmacologically active peptide sequence (X) and a stabilising peptide sequence (Z) of 4- 20 amino acid residues covalently bound to X, each amino acid residue in said stabilising peptide sequence (Z) being independently selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His, Met, Orn, and amino acid residues of the general formula I -NH-C(R')(R 2 )-C(= =0)- (I) wherein R and R are selected from the group consisting of hydrogen, Cι -6 -alkyl, phenyl, and phenyl-methyl, wherein C 1-6 -alkyl is optionally substituted with from one to three substituents selected from halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, and phenyl and phenyl-methyl is optionally substituted with from one to three substituents selected from C 1-6 -alkyl, C 2-6 -alkenyl, halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, or R 1 and R 2 together with the carbon atom to which they are bound form a cyclopentyl, cyclohexyl, or cycloheptyl ring, e.g., 2,4-diaminobutanoic acid (Dbu) and 2,3- diaminopropanoic acid (Dpr); and wherein the ratio between the half-life of said peptide conjugate and the half-life of the corresponding pharmacologically active peptide sequence, X, when treated with carboxypeptidase A or leucine aminopeptidase in about 50 mM phosphate buffer solution at about pH 7.4 at about 37°C or in plasma or serum is at least about 2, preferably at least about 3, such as at least about 5, more preferably at least about 7, such as at least about 9, e.g., at least about 10 and the ratio between the half-life of said peptide conjugate or when the pharmacologically active peptide is not orally absorbed, said conjugate is orally absorbed or a salt thereof. In one embodiment, the pharmacologically active peptide is not selected from the group consisting of H-Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu-(Lys-Glu) -OH, H-Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu-(Glu) 6 -OH, H-Tyr-Gly-Gly-Phe-Leu-(Glu) 6 -OH and H-Tyr-Gly-Gly-Phe-Leu-(Lys) 6 -OH. The present invention also relates to a composition, e.g., a pharmaceutical composition, comprising said pharmacologically active peptide conjugate and a pharmaceutically acceptable carrier, to a pharmacologically active peptide conjugate for use in therapy, a method of treating a disorder and to the use of a pharmacologically active peptide conjugate for the manufacture of a pharmaceutical composition for use in therapy. Specifically, the invention is directed to a method for inhibiting neurons from transmitting pain impulses to the spinal cord, comprising administering to a subject in need thereof a conjugate comprising enkephalin and Z in an amount effective to inhibit neurons from transmitting pain impulses, as well as the use of said conjugate for the manufacture of a pharmaceutical composition for use in treatment of pain; a method for stimulating the release of growth hormone from the pituitary comprising administering to a subject in need thereof a conjugate comprising growth hormone releasing hormone or growth hormone releasing peptide and Z in an amount effective to stimulate the release of growth hormone as well as the use of said conjugate for the manufacture of a pharmaceutical composition for use in stimulating the release of growth hormone; a method for increasing hemoglobin levels comprising administering to a subject in need thereof a conjugate comprising EMP-1 (erythropoietin mimetic protein- 1) and Z in an amount effect to increase hemoglobin levels as well as the use of said conjugate for the manufacture of a pharmaceutical composition for use in increasing treating anemia by increasing hemoglobin levels; a method for treating or preventing bone loss by altering the balance between osteoclastic (bone resorption) and osteoblast activity comprising administering to a patient in need thereof a conjugate comprising parathyroid hormone and Z in an amount effective to treat or prevent bone loss as well as use of a said conjugate for the manufacture of a pharmaceutical composition for use in treating or preventing osteoporosis; a method for reducing blood glucose levels comprising administering to a subject in need thereof a conjugate comprising glucagon-like peptide- 1 and Z in an amount effective to reduce blood sugar levels, as well as use of said conjugate in the treatment of diabetes; a conjugate comprising delta sleep inducing peptide and Z in an amount effective to prevent convulsions, act as a neuroprotectant during ischemia and act as a detoxification agent of an opiod as well as a use of said conjugate for the manufacture of a pharmaceutical composition for use in treating sleep disorders; a method for regulating production of sex hormones comprising administering to a subject in need thereof a conjugate comprising gonadotropin releasing hormone and Z in an amount effective to regulate production of sex hormones as well as use of said conjugate for the manufacture of a pharmaceutical composition for use in regulating the level of sex hormones. In another aspect the present invention relates to the use of a peptide conjugate, as defined herein, for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of a condition or disorder, where the peptide sequence X, when not bound to Z, is able to interact with a receptor (or a receptor system) involved with the condition or disorder in question, and where the interaction between X, when not bound to Z, and the receptor (or receptor system) has a therapeutic or prophylactic effect on the condition or disorder. The present invention also relates to methods for the preparation of said pharmacologically active peptide conjugate, by means of recombinant DNA-technology comprising the steps of (a) introducing a nucleic acid sequence encoding said conjugate into a host cell and (b) culturing said host cell and (c) isolating said conjugate from the culture or (a) culturing a recombinant host cell comprising a nucleic acid sequence encoding said conjugate under conditions permitting the production of said conjugate and (b) isolating said conjugate from the culture. The method also relates to methods for the preparation of said pharmacologically active peptide conjugate in which the pharmacologically active peptide X is obtained via recombinant DNA methods by isolating said peptide or from commercial sources. X is then conjugated to Z which is attached to a solid support or has been prepared by solid phase synthetic methods. Furthermore, the invention relates to the use of a stabilising peptide sequence (Z) for the preparation of a pharmacologically active peptide conjugate. DETAILED DESCRIPTION OF THE INVENTION Peptide Conjugates In the present context, the term "amino acid residue" as used in connection with X means any naturally occurring or synthetic α, β, or γ-amino acid (whether in the L-form or the D- form) as well as side-chain modified amino acids such as modified tyrosines wherein the aromatic ring is further substituted with e.g., one or more halogens, sulfono groups, nitro groups etc., and/or the phenol group is converted into an ester group, etc, including side- chain protected amino acids, wherein the amino acid side-chains are protected in accordance with methods known to the person skilled in peptide chemistry, such as described in, e.g.,, M. Bodanszky and A. Bodanszky, "The Practice of Peptide Synthesis", 2. Ed, Springer- Verlag, 1994, and J. Jones, "The Chemical Synthesis of Peptides", Clarendon Press, 1991. In the present context, the term "pharmacologically active peptide sequence" or "free peptide" as applied to X is intended to mean any peptide or peptide-containing structure, either naturally occurring or synthetic which is therapeutically or prophylactically active without the stabilising sequence Z covalently bound thereto. As defined herein, a peptide sequence is "therapeutically active" if it can be used for the treatment, remission, or attenuation of a disease state, physiological condition, symptoms or etiological indication(s) or evaluation or diagnosis thereof. A peptide sequence is "prophylactically active" if it can be used to prevent a disease state, physiological condition, symptoms or etiological indications. A pharmacologically active agent is also physiologically or biologically active. Pharmacological activity measures the effect of a substance (peptide) on physiological or biological systems in vitro, in vivo or ex vivo and may be assayed using standard in vitro, in vivo or ex vivo assays known in the art for a particular peptide or a peptide with a similar physiological function Peptides are utilised in a number of processes, e.g., cell-to-cell communication, some being present in the autonomic and central nervous system. Some of the latter peptides, and a number of other peptides, exert important effects on vascular and other smooth muscles. In a preferred embodiment, X has at the most 75 amino acid residues (or a structure corresponding to at the most 75 amino acid residues). Alternatively, X consists of at most 65, 60, 55, 53, 50, 45, 40, 35, 30, 25, 20, 15, or at the most 10 amino acid residues and consists of at least 2, preferably 5 and more preferably 10 amino acid residues. In the present context, the pharmacologically active peptide sequence X can be any peptide which in its native form is present as the C-terminal free carboxylic acid, such as Leu- enkephalin (H-Tyr-Gly-Gly-Phe-Leu-OH), or is present in its native form as a C-terminal amide, such as oxytocin (Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH 2 ), or is present in its native form as a C-terminal ester. Furthermore, the pharmacologically active peptide may also contain other special structural features such as disulfide bridges as in the case insulin. The pharmacologically active peptide may be selected from the group consisting of enkephalin, Leu-enkephalin, Met-enkephalin, angiotensin I, angiotensin II, vasopressin, endothelin, vasoactive intestinal peptide, neurotensin, endorphins, insulin, gramicidin, para- celsin, delta-sleep inducing peptide, gonadotropin-releasing hormone, human parathyroid hormone (1-34), truncated erythropoietin analogues described in Wrighton et al., 1996, Science 273:458-463), specifically EMP-1, Atrial natriuretic peptide (ANP, ANF), human brain natriuretic peptide (hBNP), cecropin, kinetensin, neurophysins, elafin, guamerin, atriopeptin I, atriopeptin II, atriopeptin III, deltorphin I, deltorphin II, vasotocin, bradykinin, dynorphin, dynorphin A, dynorphin B, growth hormone release factor, growth hormone, growth hormone releasing peptide, oxytocin, calcitonin, calcitonin gene-related peptide, calcitonin gene-related peptide II, growth hormone releasing peptide, tachykinin, adrenocorticotropic hormone (ACTH), brain natriuretic polypeptide, cholecystokinin, corticotropin releasing factor, diazepam binding inhibitor fragment, FMRF-amide, galanin, gastric releasing polypeptide, gastric inhibitory polypeptide, gastrin, gastrin releasing peptide, glucagon, glucagon-like peptide- 1, glucagon-like peptide-2, LHRH, melanin concentrating hormone, melanocyte stimulating hormone (MSH), alpha-MSH, morphine modulating peptides, motilin, neurokinin A, neurokinin B, neuromedin B, neuromedin C, neuromedin K, neuromedin N, neuromedin U, neuropeptide K, neuropeptide Y, pituitary adenylate cyclase activating polypeptide (PACAP), pancreatic polypeptide, peptide YY, peptide histidine-methionine amide (PHM), secretin, somatostatin, substance K, thyrotropin-releasing hormone (TRH), kyotorphin, melanostatin (MIF-1), thrombopoeitin analogs, in particular AF 12505 (Ile-Glu-Gly-Pro-Thr-Leu-Arg-Gln-T -Leu-Ala-Ala-Arg- Ala), insulin-like growth factor I (57-70) (Ala-Leu-Leu-Glu-Thr-Tyr-Cys-Ala-Thr-Pro- Ala-Lys-Ser-Glu), insulin-like growth factor 1(30-41) (Gly-Tyr-Gly-Ser-Ser-Ser-Arg-Arg- Ala-Pro-Gln-Thr), insulin-like growth factor 1(24-4 l)(Tyr-Phe-Asn-Lys-Pro-Thr-Gly-Tyr- Gly-Ser-Ser-Ser-Arg-Arg-Ala-Pro-Gln-Thr) , insulin-like growth factor II (33-40) (Ser-Arg- Val-Ser-Arg-Arg-Ser-Arg), insulin-like growth [tyro] factor II (33-40) (Tyr-Ser-Arg-Val- Ser-Arg-Arg-Ser-Arg), insulin-like growth factor II (69-84) (Asp-Val-Ser-Thr-Pro-Pro-Thr- Val-Leu-Pro-Asp-Asn-Phe-Pro- Arg-Tyr), growth hormone (GH)-releasing peptide-6 (GHRP-6) (His-DTrp-Ala-Trp-DPhe-Lys-NH2), beta-Interleukin I (163-171) (Val-Gln-Gly- Glu-Glu-Ser-Asn-Asp-Lys), beta-Interleukin II (44-56) (Ile-Leu-Asn-Gly-Ile-Asn-Asn-Tyr- Lys-Asn-Pro-Lys-Leu), Interleukin II (60-70) (Leu-Thr-Phe-Lys-Phe-Tyr-Met-Pro-Lys- Lys-Ala), exendin-4 (GLP-1 analog) (His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys- Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2), exendin-3 (GLP-1 analog) (His-Ser-Asp-Gly-Thr- Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Tφ- Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser), [Cys(Acm)20,31] epidermal growth factor (20-31) Cys(Acm)-Met-His-Ile-Glu-Ser-Leu-Asp-Ser-Tyr-Thr-Cys(Acm), bivalirudin (Hirulog) (D-Phe-Pro-Arg-Pro-(Gly)4-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu- Glu-Tyr-Leu), hirulog- 1 D-Phe-Pro-Arg-Pro-(Gly)4-Asn-Gly- Asp-Phe-Glu-Glu-Ile-Pro- Glu-Tyr-Leu, C-type natriuretic peptide (1-53) (CNP) (Asp-Leu- Arg- Val-Asp-Thr-Lys-Ser- Arg-Ala-Ala-Tφ-Ala-Arg-Leu-Leu-Gln-Glu-His-Pro-Asn-Ala-Arg-Lys-Tyr-Lys-Gly-Ala- Asn-Lys-Lys-Gly-Leu-Ser-Lys-Gly-Cys-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Gly-Ser-Met- Ser-Gly-Leu-Gly-Cys; Disulfide bridge: Cys37-Cys53), "Mini ANP" (Met-Cys-His- cyclohexylAla-Gly-Gly-Arg-Met-Asp-Arg-Ile-Ser-Cys-Tyr-Arg, disulfide bridge cys2- cysl3), Melanotan-II (also known as MT-II, alpha-MSH4-10-NH2, or Ac-Nle4-Asp5-His6- D-Phe7-Arg8-Tφ9-Lysl0), thymosin alphal (TA1) (Ac-Ser-Asp-Ala-Ala-Val-Asp-Thr- Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu-Ala-Glu- Asn), ornipressin (also known as 8-ornithine-vasopressin, (POR-8), [Phe2,Ile3,Orn8]vasopressin), Cys-Phe-Ile-Gln-Asn-Cys-Pro-Orn-Gly-NH2, Disulfide bridge: Cysl-Cys6), octreotide (201-995) (DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol; disulfide bridge: Cys2-Cys7), eptifibatide (INTEGRILIN), calcitonin gene-related peptide (CGRP) (Ala-Cys-Asp-Thr-Ala-Thr-Cys-Val-Thr-His-Arg-Leu-Ala-Gly-Leu-Leu-Ser-Arg- Ser-Gly-Gly-Val-Val-Lys-Asn-Asn-Phe-Val-Pro-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH 2; Disulfide bridge: Cys2-Cys7), endomoφhin-1 Tyr-Pro-Tφ-Phe-NH2; endomoφhin-2 Tyr- Pro-Phe-Phe-NH , nociceptin (also known as Oφhanin FQ, Phe-Gly-Gly-Phe-Thr-Gly- Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln), angiotensinogen (1-13) (Asp-Arg-Val- Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His), adrenomodullin (1-12) (Tyr-Arg-Gln-Ser-Met- Asn-Asn-Phe-Gln-Gly-Leu-Arg), antiarrhytmic peptide (AAP) (Gly-Pro-Hyp-Gly-Ala- Gly), Antagonist G (Arg-DTφ-(nMe)Phe-DTφ-Leu-Met-NH 2 ), indolicidin (Ile-Leu-Pro- Tφ-Lys-Tφ-Pro-Tφ-Tφ-Pro-Tφ-Arg-Arg-NH 2 ), osteocalcin (37-49) (Gly-Phe-Gln-Glu- Ala-Tyr-Arg-Arg-Phe-Tyr-Gly-Pro-Val), cortistatin 29 (1-13) (Glp)-Glu-Arg-Pro-Pro-Leu- Gln-Gln-Pro-Pro-His-Arg-Asp), cortistatin 14 Pro-Cys-Lys-Asn-Phe-Phe-Tφ-Lys-Thr- Phe-Ser-Ser-Cys-Lys; Disulfide bridge: Cys2-Cysl3, PD-145065 (Ac-D-Bhg-Leu-Asp-Ile- Ile-Tφ), PD- 142893 (Ac-D-Dip-Leu-Asp-Ile-Ile-Tφ), fibrinogen binding inhibitor peptide (His-His-Leu-Gly-Gly-Ala-Lys-Gln-Ala-Gly-Asp-Val), leptin (93-105) (Asn-Val-Ile-Gln- Ile-Ser-Asn-Asp-Leu-Glu-Asn-Leu-Arg), GR 83074 (Boc-Arg-Ala-DTφ-Phe-DPro-Pro- Nle-NH 2 ), Tyr-W-MIF-1 (Tyr-Pro-Tφ-Gly-NH 2 ), parathyroid hormone related peptide (107-111) (Thr-Arg-Ser-Ala-Tφ), angiotensinogen (1-14) Asp-Arg-Val-Tyr-Ile-His-Pro- Phe-His-Leu-Val-Ile-His-Asn, Leupeptin (Ac-Leu-Leu- Arg-CHO), and any modified or truncated analogue thereof. It is well known that many pharmacologically active peptides also exert their desired pharmaceutical effect when present in a modified or truncated form. In the case of, for example, insulin, porcine insulin differ from human insulin by only one amino acid residue, the B30 amino acid in porcine insulin being Ala and the B30 amino acid in human insulin being Thr. Despite this difference, porcine insulin has been used as an effective diabetes drug for many years. In a similar way it has been found that the essential features for activity in the heptadecapeptide Porcine gastrin I are all contained in the C-terminal tetrapeptide and that essentially all pharmaceutical effects of neurotensin are associated with the C-terminal hexapeptide. Furthermore, pharmacologically active peptides, wherein one or more amide bonds have been modified, e.g., reduced, often exhibit a similar or even enhanced pharmaceutical activity; for example the Cys [CH 2 NH]Tyr analogue of somatostatin was found to be an even more potent growth hormone releasing agent than somatostatin itself, and also the transition state analogue Leu 10 ^CH(OH)CH ]Val" of angiotensin has been found to show strong inhibitory effect against the aspartic acid protease Renin. Thus, the term "modified or truncated analogue thereof is intended to mean such peptides are modified by changing and/or deleting one or more amino acid residues in the sequence of the native peptide, including modification of the side-chain, stereochemistry, and backbone in the individual amino acid residues, such as changing one or more peptide bonds (-C(=O)-NH-) into e.g., reduced forms such as (-CH(OH)-N-), (- CH 2 -N-), and other peptide bond mimetics such as (-C(=O)-N(CH 3 )-), (-C(=O)-O), (- C(=O)-CH 2 -), (-CH=CH-), (-PO 2 -NH-), (SO-CH 2 -), (SO 2 -N-), etc. This being said, it should be understood that the peptide sequence X in question should preferably comprise at least one peptide bond (preferably at least two peptide bonds (this naturally does not apply for a dipeptide)) susceptible to enzymatic degradation in order to fully take advantage of the present invention. In the present context, the term "C 1- -alkyl" used alone or as part of another group designates a straight, branched or cyclic saturated hydrocarbon group having from one to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert.butyl, n-pentyl, n-hexyl, cyclohexyl, etc. In the present context, the term "C 2- -alkenyl" designates a hydrocarbon group having from two to six carbon atoms, which may be straight, branched, or cyclic and may contain one or more double bonds, such as vinyl, allyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2- pentenyl, 4-pentenyl, 3-methyl- 1-butenyl, 2-hexenyl, 5-hexenyl, cyclohexenyl, 2,3- dimethyl-2-butenyl etc., which may have cis and/or trans configuration. The term "aryl" is intended to mean an aromatic, carbocyclic group such as phenyl or naphtyl. The term "heteroaryl" includes 5- or 6-membered aromatic monocyclic heterocyclic groups containing 1-4 heteroatoms selected from nitrogen, oxygen and sulphur, such as pyrrolyl, furyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadizolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, and aromatic bicyclic heterocyclic groups containing 1-6 heteroatoms selected from nitrogen, oxygen and sulphur, such as quinolinyl. The term "halogen" includes fluorine, chlorine, bromine, and iodine. The peptide sequence Z is the part of the peptide conjugate responsible for introduction and/or stabilisation of a certain secondary structure into the molecule which will render the compound more stable towards degradation by proteases. It is believed that Z needs to include at least 4 amino acid residues in order to introduce such a stabilising structural element. On the other hand it is also believed that a sequence of more than around 20 amino acid residues will not improved the stability further. Thus, Z is typically a peptide sequence of 4-20 amino acid residues, e.g., in the range of 4-15, more preferably in the range of 4-10 in particular in the range of 4-7 amino acid residues, e.g., of 4, 5, 6 or 7 amino acid residues. When Z is conjugated to X, the half-life of said peptide conjugate when treated with carboxypeptidase A or leucine aminopeptidase in about 50 mM phosphate buffer solution at about pH 7.4 at about 37°C or in plasma or serum is at least about 2, preferably at least about 3, such as at least about 5, more preferably at least about 7, such as at least about 9, e.g., at least about 10 more than the half-life of X when not conjugated to Z. Furthermore, when the pharmacologically active peptide X is not orally absorbed, the conjugate is orally absorbed. Each of the amino acid residues in the peptide sequence Z are independently selected from Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His, Met, Orn, and amino acids of the formula I as defined herein such as diaminobutanoic acid or diaminopropanoic acid. Preferably, the amino acid residues are selected from Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His, Orn, and Met, more preferably from Glu, Lys, and Met, especially Lys. The above-mentioned amino acids may have either D- or L-configuration, but preferably the above-mentioned amino acids have an L-configuration. As the pharmacologically active peptide sequence X usually consists exclusively of L-amino acids, it must be expected, in order to preserve a possible stabilising helix structure of the entire peptide conjugate, that a peptide sequence Z consisting only or principally of L-amino acids will be advantageous compared to a peptide sequence Z consisting only or principally of D-amino acids. Furthermore, it is envisaged that a peptide sequence Z consisting only or principally of D- amino acids may exert toxicological effects due to the resistance of D-peptides and D-amino acids towards biodegradation. Thus, illustrative examples of the peptide sequence Z are: Lys-Lys-Lys-Lys, Xaa-Lys-Lys-Lys, Lys-Xaa-Lys-Lys, Lys-Lys-Xaa-Lys, Lys-Lys-Lys- Xaa, Xaa-Xaa-Lys-Lys, Xaa-Lys-Xaa-Lys, Xaa-Lys-Lys-Xaa, Lys-Xaa-Xaa-Lys, Lys-Xaa- Lys-Xaa, Lys-Lys-Xaa-Xaa, Xaa-Xaa-Xaa-Lys, Xaa-Xaa-Lys-Xaa, Xaa-Lys-Xaa-Xaa, Lys- Xaa-Xaa-Xaa, Xaa-Xaa-Xaa-Xaa, Lys-Lys-Lys-Lys-Lys, Xaa-Lys-Lys-Lys-Lys, Lys-Xaa- Lys-Lys-Lys, Lys-Lys-Xaa-Lys-Lys, Lys-Lys-Lys-Xaa-Lys, Lys-Lys-Lys-Lys-Xaa, Xaa- Xaa-Lys-Lys-Lys, Xaa-Lys-Xaa-Lys-Lys, Xaa-Lys-Lys-Xaa-Lys, Xaa-Lys-Lys-Lys-Xaa, Lys-Xaa-Xaa-Lys-Lys, Lys-Xaa-Lys-Xaa-Lys, Lys-Xaa-Lys-Lys-Xaa, Lys-Lys-Xaa-Xaa- Lys, Lys-Lys-Xaa-Lys-Xaa, Lys-Lys-Lys-Xaa-Xaa, Lys-Lys-Xaa-Xaa-Xaa, Lys-Xaa-Lys- Xaa-Xaa, Lys-Xaa-Xaa-Lys-Xaa, Lys-Xaa-Xaa-Xaa-Lys, Xaa-Lys-Lys-Xaa-Xaa, Xaa-Lys- Xaa-Xaa-Lys, Xaa-Xaa-Lys-Lys-Xaa, Xaa-Xaa-Lys-Xaa-Lys, Xaa-Xaa-Xaa-Lys-Lys, Lys- Xaa-Xaa-Xaa-Xaa, Xaa-Lys-Xaa-Xaa-Xaa, Xaa-Xaa-Lys-Xaa-Xaa, Xaa-Xaa-Xaa-Lys-Xaa, Xaa-Xaa-Xaa-Xaa-Lys, Xaa-Xaa-Xaa-Xaa-Xaa, Lys-Lys-Lys-Lys-Lys-Lys, Xaa-Lys-Lys- Lys-Lys-Lys, Lys-Xaa-Lys-Lys-Lys-Lys, Lys-Lys-Xaa-Lys-Lys-Lys, Lys-Lys-Lys-Xaa- Lys-Lys, Lys-Lys-Lys-Lys-Xaa-Lys, Lys-Lys-Lys-Lys-Lys-Xaa, Xaa-Xaa-Lys-Lys-Lys- Lys, Xaa-Lys-Xaa-Lys-Lys-Lys, Xaa-Lys-Lys-Xaa-Lys-Lys, Xaa-Lys-Lys-Lys-Xaa-Lys, Xaa-Lys-Lys-Lys-Lys-Xaa, Lys-Xaa-Xaa-Lys-Lys-Lys, Lys-Xaa-Lys-Xaa-Lys-Lys, Lys- Xaa-Lys-Lys-Xaa-Lys, Lys-Xaa-Lys-Lys-Lys-Xaa, Lys-Lys-Xaa-Xaa-Lys-Lys, Lys-Lys- Xaa-Lys-Xaa-Lys, Lys-Lys-Xaa-Lys-Lys-Xaa, Lys-Lys-Lys-Xaa-Xaa-Lys, Lys-Lys-Lys- Xaa-Lys-Xaa, Lys-Lys-Lys-Lys-Xaa-Xaa, Xaa-Xaa-Xaa-Lys-Lys-Lys, Xaa-Xaa-Lys-Xaa- Lys-Lys, Xaa-Xaa-Lys-Lys-Xaa-Lys, Xaa-Xaa-Lys-Lys-Lys-Xaa, Xaa-Lys-Xaa-Xaa-Lys- Lys, Xaa-Lys-Xaa-Lys-Xaa-Lys, Xaa-Lys-Xaa-Lys-Lys-Xaa, Xaa-Lys-Lys-Xaa-Xaa-Lys, Xaa-Lys-Lys-Xaa-Lys-Xaa, Xaa-Lys-Lys-Lys-Xaa-Xaa, Lys-Lys-Lys-Xaa-Xaa-Xaa, Lys- Lys-Xaa-Lys-Xaa-Xaa, Lys-Lys-Xaa-Xaa-Lys-Xaa, Lys-Lys-Xaa-Xaa-Xaa-Lys, Lys-Xaa- Lys-Lys-Xaa-Xaa, Lys-Xaa-Lys-Xaa-Lys-Xaa, Lys-Xaa-Lys-Xaa-Xaa-Lys, Lys-Xaa-Xaa- Lys-Lys-Xaa, Lys-Xaa-Xaa-Lys-Xaa-Lys, Lys-Xaa-Xaa-Xaa-Lys-Lys, Lys-Lys-Xaa-Xaa- Xaa-Xaa, Lys-Xaa-Lys-Xaa-Xaa-Xaa, Lys-Xaa-Xaa-Lys-Xaa-Xaa, Lys-Xaa-Xaa-Xaa-Lys- Xaa, Lys-Xaa-Xaa-Xaa-Xaa-Lys, Xaa-Lys-Lys-Xaa-Xaa-Xaa, Xaa-Lys-Xaa-Lys-Xaa-Xaa, Xaa-Lys-Xaa-Xaa-Lys-Xaa, Xaa-Lys-Xaa-Xaa-Xaa-Lys, Xaa-Xaa-Lys-Lys-Xaa-Xaa, Xaa- Xaa-Lys-Xaa-Lys-Xaa, Xaa-Xaa-Lys-Xaa-Xaa-Lys, Xaa-Xaa-Xaa-Lys-Lys-Xaa, Xaa-Xaa- Xaa-Lys-Xaa-Lys, Xaa-Xaa-Xaa-Xaa-Lys-Lys, Lys-Xaa-Xaa-Xaa-Xaa-Xaa, Xaa-Lys-Xaa- Xaa-Xaa-Xaa, Xaa-Xaa-Lys-Xaa-Xaa-Xaa, Xaa-Xaa-Xaa-Lys-Xaa-Xaa, Xaa-Xaa-Xaa- Xaa-Lys-Xaa, Xaa-Xaa-Xaa-Xaa-Xaa-Lys, Xaa-Xaa-Xaa-Xaa-Xaa-Xaa, wherein each Xaa is independently selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Arg, His, Met, Orn, and amino acids of the formula I as defined herein, e.g., Dbu or Dpr. The stabilising peptide sequence Z may in one embodiment, have an overall charge in the range from about 0 to +15, preferably in the range from 0 to +10, e.g., from 0 to +8, in particular from about 0 to +6, such as from about 0 to +4, e.g., from 0 to +3, at pH 7. Without being bound by any specific theory, it is envisaged that the non-negative charge at the stabilising peptide sequence Z may also to some extend facilitate transportation to and over cell membranes which possess a negative potential at the extracellular site. Thus, in order to secure a non-negative overall charge on the stabilising peptide sequence Z, the peptide sequence Z preferably comprises at least one Lys amino acid residue, more preferably at least two Lys amino acid residues, such as at least three Lys amino acid residues, e.g., at least four Lys amino acid residues, even more preferably at least five Lys amino acid residues, such as at least six Lys amino acid residues. As indicated above, the amino acid residues of Z may of course all be different or all be identical. However, in interesting embodiments of the present invention, the amino acid residues in Z are selected from two or three different amino acids, or are identical amino acids. Examples of suitable peptide sequences, wherein the amino acid residues in Z are identical are e.g., (Lys) n , wherein n is an integer in the range from 4 to 15, preferably in the range from 4 to 10, such as in the range from 4 to 8, e.g., in the range from about 4 to 6, e.g., Lys 4 , Lys 5 or Lys . Examples of suitable peptide sequences, wherein the amino acid residues in Z are selected from about two different amino acids are e.g.,, (Lys-Xaa) m or (Xaa-Lys) m , wherein m is an integer in the range from about 2 to 7, preferably in the range from 2 to 5, such as in the range from 2 to 4, e.g., 3, and Xaa is independently selected from the group consisting of Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Arg, His, Orn, 2,4- diaminobutanoic acid, 2,3-diaminopropanoic acid and Met. More preferably such peptide sequences are e.g., (Lys-Xaa) 3 or (Xaa-Lys) 3 , wherein Xaa is as defined above, such as (Lys-Glu) 3 or (Glu-Lys) 3 . Other examples of suitable peptide sequences, wherein the amino acid residues in Z are selected from about two amino acid residues are e.g., Lys p -Xaa q or Xaa p -Lys q , wherein p and q are integers in the range froml to 14, with the proviso that p+q is in the range from 4 to 15, preferably in the range from 4 to 10, such as in the range from 4 to 8, e.g., in the range from 4 to 6, e.g., 4, 5 or 6, and Xaa is independently selected from the group consisting of Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Arg, His and Met. More preferably such peptide sequences are e.g., Lys 3 -Xaa 3 or Xaa 3 -Lys 3 , wherein Xaa is as defined above, such as Lys 3 -Glu 3 or Glu 3 -Lys 3 . Examples of suitable peptide sequences, wherein the amino acid residues in Z are selected from three different amino acids are e.g., Xaa'-(Lys) x -(Xaa 2 ) y , Xaa 1 -(Xaa 2 ) x -(Lys) y , (Lys) x - (XaaVXaa 1 , (Xaa') x -(Lys) y -Xaa 2 , (Lys) x -Xaa'-(Xaa 2 ) y , (Xaa') x -Xaa 2 -(Lys) y , Xaa'-Lys- Xaa 2 -Lys, Xaa 1 -Lys-Xaa 2 -Lys-Xaa 2 , Xaa 1 -Lys-Xaa 2 -Lys-Xaa 2 -Lys, Xaa'-Xaa 2 -Lys-Xaa 2 , Xaa 1 -Xaa 2 -Lys-Xaa 2 -Lys, Xaa'-Xaa 1 -Lys-Xaa 2 -Lys-Xaa 2 , Lys-Xaa 2 -Lys-Xaa', Lys-Xaa 2 - Lys-Xaa 2 -Xaa', Lys-Xaa 2 -Lys-Xaa 2 -Lys-Xaa', Xaa 2 -Lys-Xaa 2 -Xaa', Xaa 2 -Lys-Xaa 2 -Lys- Xaa 1 , Xaa 2 -Lys-Xaa'-Lys-Xaa 2 -Xaa 1 , etc., wherein x and y are integers in the range from about 1 to 4 with the proviso that x+y is at the most 5, and Xaa 1 and Xaa 2 is independently selected from about the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Arg, His, Met, Orn, 2,3-diaminopropanoic acid, 2,4-diaminobutanoic acid and amino acids of the formula I as defined herein. With respect to the peptide sequence Z, it is envisaged that the specific amino acid residues mentioned as constituents of the peptide sequence Z, i.e. Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His, Met, Orn, 2,3-diaminopropanoic acid (Dpr), 2,4-diaminobutanoic acid (Dbu) and amino acid residues of the formula I as defined herein, are amino acid residues which, due to their sterical arrangement around the α-carbon atom, and probably also due to a specific electronic configuration, have certain preferences for participating in, or even stabilising or initiating, helix-like structures. The Chou-Fasman approach (Chou, P.Y. & Fasman, G.D. Ann. Rev. Biochem. 47, 251-276 (1978)) is one attempt to quantify (empirically) the likelihood for a specific amino acid residue to be involved in an α-helix structure (expressed as the "Conformational parameter P α "). Chou and Fasman's studies and related studies have, however, shown that amino acid residues which have a low parameter P α , may be found in α-helices, but of course not as often as amino acid residues having a higher P α . Thus, in the peptide sequence Z, it is considered possible to include a small proportion of amino acid residues which are not among the amino acid residues selected above as constituents of Z, and still obtain the desired effect from the peptide sequence Z, in that the selected amino acid residues are believed to compensate for any negative or neutral effect of such an alternative amino acid residue. In a specific embodiment, Z is (Dbu) n or (Dpr) n , wherein n is an integer in the range from about 4 to 15, preferably in the range from about 4 to 10, such as in the range from about 4 to 8, e.g., in the range from about 4 to 6. In a most specific embodiment, Z is Dpr . Thus, in embodiments which are within the scope of the present invention, it may be realistic to include up to 25% of amino acid residues which are not among the amino acids preferred as constituents of Z. (By "25% percent" is referred to the number of amino acid residues, i.e. no alternative amino acid residues are allowed in di- and tripeptides, up to one alternative amino acid residue is allowed in tetra-, penta-, hexa-, and heptapeptides, up to two alternative amino acid residues are allowed in octapeptides, etc.). Such alternative amino acid residues may be selected from Val. He, Pro, Phe, Gly, Tφ, as well as N-methyl amino acid residues, however, preferably not Pro, Gly and N-methyl amino acid residues. Moreover, the C-terminal of Z may be in the form of the free acid, the amide, or an ester, e.g., methyl ester, ethyl ester, benzyl ester, etc., depending on the type of solid support material and cleavage conditions used in connection with the syntheses of the peptide conjugates as will be clear to the person skilled in the art. The N-terminal may be in the form of the free amine or a lactam. The stabilising peptide sequence Z may be bound to the C-terminal or the N-terminal of the pharmacologically active peptide sequence, X, or two peptide sequences may be bound individually to both the C- and N-terminal of X. In case the native pharmacologically active peptide X possesses a free C-terminal carboxylic acid (as in the case of Leu- enkephalin), the peptide sequence Z may be attached to either the C-terminal of the peptide X or to the N-terminal of the peptide X, or the C- and N-terminal of X may both be bound to each individual peptide sequence Z. Alternatively, Z may be bound to the nitrogen atom on the side chain of lysine, histidine or arginine or a carbonyl function on the side chain of glutamic acid or aspartic acid anywhere within the peptide sequence X. In one embodiment, Z may be attached to X within the sequence and to the N- an or C-terminal of X. Whether the sequence should be attached to the peptide sequence X at its C-terminal, at its N-terminal, or both, or within the peptide sequence X depends on the specific peptide X and the pharmaceutical function that said peptide X exerts and can be easily determined by the person skilled in the art. In some cases, the biological or physiological activity may depend crucially on the negative charge at the C-terminal of the pharmacologically active peptide X. Accordingly, in such cases, the activities and consequently pharmacological effect of X may be obstructed by blocking the negative charge on the C-terminal of the pharmacologically active peptide X and it may therefore be advantageous to attach the peptide sequence Z to the N-terminal of the peptide X. In a similar way, in cases where the pharmacologically active peptide X is present in its native form as a C-terminal amide (such as oxytocin) it may be advantageous to attach the stabilising peptide sequence Z to the N- terminus of the peptide X if it is believed that the amide group has an important pharmacological function. Thus, it should be understood that any peptide sequences corresponding to pharmacologically active peptides X having a free C-terminal carboxyl group as well as peptides corresponding to pharmacologically active peptides X having a C- terminal amide or ester group may be used in the peptide conjugates of the invention. However, in an interesting embodiment of the invention the peptide sequence Z is attached to the C-terminal of the pharmacologically active peptide X (whether X in its native form is a free carboxylic acid, an amide or an ester). It should be understood that the peptide conjugates of the invention might also be in the form of a salt thereof. Salts include pharmaceutically acceptable salts, such as acid addition salts and basic salts. Examples of acid addition salts are hydrochloride salts, sodium salts, calcium salts, potassium salts, etc. Examples of basic salts are salts where the cation is selected from alkali metals, such as sodium and potassium, alkaline earth metals, such as calcium, and ammonium ions "* N (R 3 ) 3 (R ), where R and R 4 independently designates optionally substituted Cι- -alkyl, optionally substituted C 2- -alkenyl, optionally substituted aryl, or optionally substituted heteroaryl. Other examples of pharmaceutically acceptable salts are; e.g., those described in "Remington's Pharmaceutical Sciences" 17. Ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, U.S.A., 1985 and more recent editions, and in Encyclopedia of Pharmaceutical Technology. In a most specific embodiment, the peptide conjugate is selected from the group consisting of H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg- Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala- Arg-Ala-Arg-Leu-Lys6-NH2 (GHRH( 1 -44)(Human)-Lys6-NH2); H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg- Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala- Arg-Ala-Arg-Leu-Glu6-NH2 (GHRH (l-44)(Human)-Glu6-NH2); H- Lys 6 .Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met- Glu-Arg-Val-Glu-Tφ-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-OH (Lys6-PTH( 1 - 34)(Human)-OH); H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu- Arg-Val-Glu-Tφ-Leu-Arg-Lys-Lys-Leu-Gln-Asp- Val-His-Asn-Phe-Lys6-OH (PTH( 1 - 34)(Human)-Lys6-OH); H-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys- Glu-Phe-Ile-Ala-Tφ-Leu-Val-Lys-Gly-Arg-Lys6-OH (GLP-l-(7-36)(Human)-Lys6-OH); H-Gly-Gly-Thr-Tyr-Ser-Cγs(Acm)-His-Phe-Gly-Pro-Leu-Thr-Tφ-Val-Cys(Acm)-Lys-Pro- Gln-Gly-Gly-Lys6-OH (EMP-1 -Lys6-OH); H- Lys6-Gly-Gly-Thr-Tyr-Ser-Cys(Acm)-His-Phe-Gly-Pro-Leu-Thr-Tφ-Val-Cys(Acm)- Lys-Pro-Gln-Gly-Gly-OH (Lys6-EMP- 1 -OH); H-Aib-His-2-D-Nal-D-Phe-Lys-(Lys)6-NH2 (GHRP-(Lys)6-NH2); H-Tyr-Gly-Gly-Phe-Leu-Lys-Lys-Glu-Glu-Glu-Lys-OH (Leu-enkephalin-Lys-Lys-Glu- Glu-Glu-Lys-OH); H-Tyr-Gly-Gly-Phe-Leu-Lys-Glu-Glu-Glu-Glu-Lys~OH (Leu-enkephalin-Lys-Glu-Glu- Glu-Glu-Lys-OH); H-Tyr-Gly-Gly-Phe-Leu-Lys-Glu-Glu-Glu-Glu-Lys-OH (Leu-enkephalin-(Lys-Glu) 3 ; H-Tyr-Gly-Gly-Phe-Leu-(Dpr)6-OH (Leu-enkephalin-(Dpr)6-OH); H-Lys,-Tyr-Gly-Gly-Phe-Leu-OH (H-Lys 6 -Leu-enkephalin); H-Tyr-Gly-Gly-Phe-Leu- Lys 6 -OH (H-Leu-enkephalin-Lys ); H-Lys 6 -Tyr-Gly-Gly-Phe-Leu-Lys 6 -OH (H-Lys 6 -Leu-enkephalin-Lys -OH); Glu-His-Tφ-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-(Lys) 6 -OH (GnRH-Lys 6 -OH); Glu-His-Tφ-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-(Lys-Glu) 3 -OH (GnRH-(Lys-Glu) 3 -OH); and H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu- Arg-Val-Glu-Tφ-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-(Lys-Glu) 3 -OH (PTH 1-34 human-(Lys-Glu) 3 -OH). As explained above, the peptide sequence Z is the part of the peptide conjugate responsible for introducing of a certain structure into the molecule which will render the compound more stable towards protease-catalysed degradation. Therefore, the present invention also relates to the use of a stabilising peptide sequence (Z) as defined above for the preparation of a pharmacologically active peptide conjugate as defined above. As mentioned previously, the routes of administration of pharmacologically active peptides have thus far been rather limited due to the fast biodegradation by proteases such as chymotrypsin, trypsin, carboxypeptidase A, pepsin, leucine aminopeptidase, etc. Thus, the requirements to the pharmacologically active peptide conjugates suitable for the demanding puφose is that on the one hand, the peptide conjugate should, at least to some extend, be able to resist protease-catalysed hydrolysis, and one the other hand, the peptide conjugate should still, at least to some extend, be able to exert the desired pharmaceutical effect normally provided by the free peptide X. On this basis, in vitro assays have been developed which give an assessment of the capacity of a peptide conjugate to exert the desired properties. Such assays, as well as the results thereof, are illustrated in the examples. These types of assays are excellent preliminary tests which can be easily performed by the person skilled in the art to assess the suitability of any given peptide conjugate prepared according to the principles disclosed herein. Thus, the tendency of the pharmacologically active peptide conjugates of the invention to resist protease-catalysed hydrolysis can be measured directly by the in vitro enzyme assays shown in the examples. The tendency of the peptide conjugate to resist degradation can for example be expressed as a pseudo-first-order rate constant and/or as the half-life of said peptide conjugates, which can then be compared to the corresponding values of the free peptide X. As will be apparent from the examples provided herein, it has been found that it is possible to obtain a remarkable increase in the half-life (tι/ 2 ) of a pharmacologically active peptide sequence by conjugating the peptide (X) in question with a stabilising peptide sequence (Z) according to the invention. Thus, in a preferred embodiment of the invention, the ratio between the half-life of the peptide conjugate in question in the "Hydrolysis in enzyme solution test", as defined herein, and the half-life of the corresponding free peptide (X), in the "Hydrolysis in enzyme solution test", is at least about 2, preferably at least about 3, such as at least about 5, more preferably at least about 10, especially at least about 20, such as at least about 50, e.g., at least about 100, when using carboxypeptidase A or leucine aminopeptidase. Although the proteases carboxypeptidase A and leucine aminopeptidase have been used in the tests described herein, it is envisaged that the ability of the peptide conjugates to resist protease degradation may also be tested in identical or similar test systems using other endo- or exopeptidases, such as trypsin, or mixtures of such peptidases, e.g., artificial gastric juice. Furthermore, the ability of the peptide conjugates of the invention to exert the desired pharmaceutical effect was tested in various in vitro and in vivo assay procedures disclosed herein. Thus, preferred peptide conjugates are such conjugates which exert some pharmaceutical effect, preferably a similar and in some cases even an enhanced pharmaceutical effect compared to the pharmacologically active free peptide (X). As will be understood from examples provided herein, the peptide conjugates of the invention are able to "survive" various proteolytic barriers present in the gastrointestinal environment. Thus, as demonstrated in the examples herein, it is possible to administer a pharmacologically active peptide conjugate (e.g., orally) as some fraction of the administered peptide conjugate (e.g., at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or even at least 99%) of the total amount peptide conjugate administered) is able to enter the blood stream. Therefore, especially interesting peptide conjugates of the invention are such compounds which when administered orally in a pharmacologically effective dose (which of course depends on the actual illness or disorder to be treated and the actual peptide or peptide conjugate selected for said treatment) is present in the blood stream in a therapeutically or prophylactically effective concentration after a period of from about 0.1 min to 24 hrs., 0.1 min to 5 hours, e.g., after a period of from about 0.5 min to 3 hours, such as from about 1 min to 2 hours, preferably after a period from about 3 min to 1 hour, such as from about 5 min to 1 hour, e.g., from about 10 min to 1 hour, 1 min.-16 hrs, 0.1 min-12 hrs. Therapeutically relevant concentrations of said peptide conjugates will, of course, depend on the actual illness or disorder to be treated, and such therapeutically relevant concentrations will be known to the person skilled in the art. Moreover, the peptide conjugates of the invention are suφrisingly stable in e.g., blood serum and plasma. Thus, preferred peptide conjugates of the invention are such compounds which have a half-life in human or mice serum or plasma (optionally containing a buffer to secure a certain pH, e.g., a pH at 7.4) at 37°C of at least about 10 minutes, such as at least about 15 min, e.g., at least about 0.5 h, preferably at least about 1 h, such as at least about 2 h, e.g., at least about 3 h, more preferably at least about 4 h, such as at least about 5 h, e.g., at least about 6 h, in particular at least about 12 h, such as at least about 24 h, e.g., at least about 36 h. Especially preferred is where the ratio of half-life of said peptide conjugate and the half-life of the corresponding pharmacologically active peptide sequence, X, in plasma or serum is at least about 2, preferably at least about 3, such as at least about 5, more preferably at least about 7, such as at least about 9, e.g., at least about 10. Compositions The invention also concerns a composition comprising a pharmacologically active peptide conjugate as defined above in combination with a pharmaceutically acceptable carrier. Such compositions may be in a form adapted to oral, subcutaneous, parenteral (intravenous, intraperitoneal), intramuscular, rectal, epidural, intratracheal, intranasal, dermal, vaginal, buccal, ocularly, direct brain or pulmonary administration, preferably in a form adapted to oral administration, and such compositions may be prepared in a manner well-known to the person skilled in the art, e.g., as generally described in "Remington's Pharmaceutical Sciences", 17. Ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, U.S.A., 1985 and more recent editions and in the monographs in the "Drugs and the Pharmaceutical Sciences" series, Marcel Dekker. The compositions may appear in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or topical applications. The pharmaceutical carrier or diluent employed may be a conventional solid or liquid carrier. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. If a solid carrier isused for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about about 25 mg to about 1 g. A typical tablet which may be prepared by conventional tabletting techniques may contain: Core: active compound (as free compound or salt thereof) 100 mg; colloidal silicon dioxide (Aerosil) 1.5 mg; cellulose, microcryst. (Avicel) 70 mg; modified cellulose gum (Ac-Di- Sol) 7.5 mg; magnesium stearate. Coating: HPMC approx. 9 mg; *Mywacett 9-40T approx. 0.9 mg; *acylated monoglyceride used as plasticizer for film coating. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution. For nasal administration, the preparation may contain a conjugate of the present invention dissolved or suspended in a liquid carrier, in particular, an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents, e.g., propylene glycol, surfactants such as bile acid salts or polyoxyethylene higher alcohol ethers, absoφtion enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabines. The composition may also be in a form suited for local or systemic injection or infusion and may, as such, be formulated with sterile water or an isotonic saline or glucose solution. The compositions may be sterilized by conventional sterilization techniques which are well known in the art. The resulting aqueous solutions may be packaged for use or filtered under aseptic conditions and lyophilized, the lyophilized preparation being combined with the sterile aqueous solution prior to administration. The composition may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as buffering agents, tonicity adjusting agents and the like, for instance sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, etc. The invention also concerns a pharmacologically active peptide conjugate as defined above for use in therapy, and the use of a pharmacologically active peptide conjugate as defined above for the manufacture of a pharmaceutical composition for use in therapy, e.g., in the treatment of disorders in the central nervous system, in vaccine therapy, and in the treatment of HIV, cancer, diabetes, incontinence, hypertension, amnesia, Alzheimer's disease, fever, depression, sex hormone regulation, eating, schizophrenia, osteoporosis and insomnia., and as analgesics and contraceptives, and such indications known to be treated by therapy comprising administration of pharmacologically active peptides. In specific embodiments, a conjugate comprising enkephalin and Z may be used to inhibit neurons from transmitting pain impulses, a conjugate comprising growth hormone releasing hormone or growth hormone releasing peptide and Z may be used to stimulate the release of growth hormone, for use in stimulating the release of growth hormone, a conjugate comprising EMP-1 and Z may be used to increase hemoglobin levels a conjugate comprising parathyroid hormone and Z may be used to treat or prevent bone loss, a conjugate comprising glucagon-like peptide- 1 and Z may be used in the treatment of diabetes, a conjugate comprising delta sleep inducing peptide and Z may be used for treating sleep disorders and a conjugate comprising gonadotropin releasing hormone and Z may be used to regulate sex hormones. As mentioned above, a major obstacle to the application of peptides as clinically useful drugs is their poor delivery characteristics since most peptides are rapidly metabolised by proteolysis at most routes of administration. Consequently, a very interesting prospect of the present invention is that it is possible to prepare pharmacologically active peptide conjugates for the treatment of mammals, such as humans, which are stabilised towards degradation by proteases and, at the same time, are able to exert a pharmaceutical effect in the environment in which the free peptide (X) will exhibit a pharmaceutical action. Accordingly, the present invention also relates to the use of a pharmacologically active peptide conjugate as defined above for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of a condition or disorder, where the peptide sequence X, when not bound to Z, is able to interact with a receptor (or a receptor system) involved with the condition or disorder in question, and where the interaction between X, when not bound to Z, and the receptor (or receptor system) has a therapeutic or prophylactic effect on the condition or disorder. Thus, it should be understood that a peptide conjugate of the present invention may substitute the corresponding free peptide (X) in e.g., therapies where the free peptide X is administrated intravenous since the peptide conjugates of the invention may be administered in a more convenient way, e.g., orally, as said peptide conjugates are able to overcome proteolytic barriers prevailing in the body. In a similar way, the peptide conjugates of the invention may be used in therapies where it has not previously been possible to use the corresponding free peptide (X) as X has been readily degraded in or secreted from the body. Preparation of Conjugates The peptide conjugates of the invention may be prepared by methods known per se in the art. Thus, the peptide sequences X and Z may be prepared by standard peptide-preparation techniques such as solution synthesis or Merrifield-type solid phase synthesis. In one possible synthesis strategy, the peptide conjugates of the invention may be prepared by solid phase synthesis by first constructing the peptide sequence Z using well-known standard protection, coupling and deprotection procedures, thereafter sequentially coupling the pharmacologically active sequence X on Z in a manner similar to the construction of Z, and finally cleaving off the entire peptide conjugate from the carrier. This strategy yields a peptide conjugate, wherein the stabilising peptide sequence Z is covalently bound to the pharmacologically active peptide X at the C-terminal carbonyl function of X. If the desired peptide conjugate, however, is a peptide conjugate, wherein two stabilising sequences Z are covalently and independently bound to both the C- and the N-terminal of the pharmacologically active peptide X, the above strategy is also applicable but, as will be understood by the person skilled in the art, before cleaving the off the C-terminal bound peptide conjugate from the solid support, it is necessary to sequentially couple the second stabilising peptide sequence Z to the N-terminal of X in a manner similar to the procedure described above. This strategy may also be used to attach Z to the carbonyl function on the side chain of Glu or Asp. A possible strategy for the preparation of peptide conjugates, wherein the stabilising peptide sequence Z is covalently bound to the N-terminal nitrogen atom or covalently bound to the nitrogen atom on the side chain of Lys, Arg or His of X is analogous with the method described above, i.e. said peptide conjugates may be prepared by solid phase synthesis by first constructing the pharmacologically active peptide sequence X using well-known standard protection, coupling and deprotection procedures, thereafter sequentially coupling the stabilising peptide sequence Z on X in a manner similar to the construction of X, and finally cleaving off the entire peptide conjugate from the carrier. Another possible strategy is to prepare one or both of the two sequences X and Z (or parts thereof) separately by solution synthesis, solid phase synthesis, recombinant techniques, or enzymatic synthesis, followed by coupling of the two sequences by well-known segment condensation procedures, either in solution or using solid phase techniques or a combination thereof. In one embodiment, X may be prepared by recombinant DNA methods and Z may be prepared by solid phase synthesis. The conjugation of X and Z may be carried out by using chemical ligation. This technique allows for the assembling of totally unprotected peptide segments in a higly sepcific manner (Liu et al., 1996, J. Am. Chem. Soc. 118:307- 312 and Dawson et al., 1996, 226:776). The conjugation can also be performed by protease-catalysed peptide bond formation, which offers a highly specifc technique to combine totally unprotected peptide segments via a peptide bond (W. Kullmann, 1987, Enzymatic Peptide Synthesis, CRC Press, Boca Raton, Florida, pp. 41-59. Side chain derivatization of Lys, Arg, His, Tφ, Ser, thr, Cys, Tyr, Asp and Glu with the stabilising peptide sequence, Z can be carried out by traditional convergent peptide synthesis using suitable orthogonal protecting schemes as known in the art, or by using the equally well known general solid phase method with suitable orthogonal removable side chain protection. Furthermore, it is envisaged that a combination of the above-mentioned strategies may be especially applicable where a modified peptide sequence, e.g., from a pharmacologically active peptide comprising isosteric bonds such as reduced peptide bonds or N-alkylated peptide bonds, is to be coupled to a peptide sequence Z. In this case, it may be advantageous to prepare the immobilised fragment of Z by successive coupling of amino acids, and then couple a complete pharmacologically active peptide sequence X (prepared in solution or fully or partially using solid phase techniques or by means of recombinant techniques) to the fragment. Examples of suitable solid support materials (SSM) are e.g., functionalised resins such as polystyrene, polyacrylamide, polydimethylacrylamide, polyethyleneglycol, cellulose, polyethylene, polyethyleneglycol grafted on polystyrene, latex, dynabeads, etc. It should be understood that it may be necessary or desirable that the C-terminal amino acid of the peptide sequence Z or the C-terminal amino acid of the pharmacologically active peptide X is attached to the solid support material by means of a common linker such as 2,4-dimethoxy-4'-hydroxy-benzophenone, 4-(4-hydroxy-methyl-3-methoxyphenoxy)- butyric acid, 4-hydroxy-methylbenzoic acid, 4-hydroxymethyl-phenoxyacetic acid, 3-(4- hydroxymethylphenoxy)propionic acid, and p-[(R,S)-a[l-(9H-fluoren-9- yl)methoxyformamido]-2,4-dimethoxybenzyl]-phenoxy-acetic acid. The peptide conjugates of the invention may be cleaved from the solid support material by means of an acid such as trifluoracetic acid, trifluoromethanesulfonic acid, hydrogen bromide, hydrogen chloride, hydrogen fluoride, etc. optionally in combination with one or more "scavengers" suitable for the puφose, e.g., ethanedithiol, triisopropylsilane, phenol, thioanisole, etc., or the peptide conjugate of the invention may be cleaved from the solid support by means of a base such as ammonia, hydrazine, an alkoxide, such as sodium ethoxide, an hydroxide, such as sodium hydroxide, etc. Thus, the present invention also relates to a method for the preparation of a pharmacologically active peptide conjugate, wherein Z is covalently bound to X at the C- terminal function of X (X-Z), comprising the steps of: a) coupling an N-α-protected amino acid in the carboxyl activated form, or an N-α- protected dipeptide in the C-terminal activated form to an immobilised peptide sequence H- Z-SSM, thereby forming an immobilised N-α-protected peptide fragment, b) removing the N-α-protecting group, thereby forming an immobilised peptide fragment having an unprotected N-terminal end, c) coupling an additional N-α-protected amino acid in the carboxyl activated form, or an additional N-α-protected dipeptide in the C-terminal activated form to the N-terminal end of the immobilised peptide fragment, and repeating the removal/coupling step procedure in step b) and c) until the desired peptide sequence X is obtained, and then d) cleaving off the peptide conjugate from the solid support material. In a further aspect the present invention also relates to a method for the preparation of a pharmacologically active peptide conjugate, wherein Z is covalently bound to the N- terminal nitrogen atom of X (Z-X), comprising the steps of: a) coupling an N-α-protected amino acid, or an N-α-protected dipeptide to a solid support material (SSM), thereby forming an immobilised N-α-protected amino acid, or an immobilised N-α-protected dipeptide fragment, b) removing the N-α-protecting group, thereby forming an immobilised amino acid or peptide fragment having an unprotected N-terminal end, c) coupling an additional N-α-protected amino acid in the carboxyl activated form, or an additional N-α-protected dipeptide in the C-terminal activated form to the N-terminal end of the immobilised amino acid or peptide fragment, and repeating the removal/coupling step procedure in step b) and c) until the desired peptide sequence X is obtained, d) coupling an additional N-α-protected amino acid in the carboxyl activated form, or an additional N-α-protected dipeptide in the C-terminal activated form to the N-terminal end of the immobilised peptide fragment, and repeating the removal/coupling step procedure in step b) and d) until the desired peptide sequence Z is obtained, and then e) cleaving off the peptide conjugate from the solid support material. In a still further aspect the present invention relates to a method for the preparation of a pharmacologically active peptide conjugate, wherein a first sequence (Z) is covalently bound to X at the C-terminal function of X and a second sequence (Z) is covalently bound to the N-terminal nitrogen atom of X (Z-X-Z), comprising the steps of: a) coupling an N-α-protected amino acid in the carboxyl activated form, or an N-α- protected dipeptide in the C-terminal activated form to an immobilised peptide sequence H- Z-SSM, thereby forming an immobilised N-α-protected peptide fragment, b) removing the N-α-protecting group, thereby forming an immobilised peptide fragment having an unprotected N-terminal end, c) coupling an additional N-α-protected amino acid in the carboxyl activated form, or an additional N-α-protected dipeptide in the C-terminal activated form to the N-terminal end of the immobilised peptide fragment, and repeating the removal/coupling step procedure in step b) and c) until the desired peptide sequence X is obtained, and then d) coupling an additional N-α-protected amino acid in the carboxyl activated form, or an additional N-α-protected dipeptide in the C-terminal activated form to the N-terminal end of the immobilised peptide fragment, and repeating the removal/coupling step procedure in step b) and d) until the desired peptide sequence Z is obtained, and then e) cleaving off the peptide conjugate from the solid support material. The coupling, removal and cleavage steps are performed by methods known to the person skilled in the art taking into consideration the protection strategy and the selected solid phase material. In general, however, it is believed that the Boc (tert.butyloxycarbonyl) as well as the Fmoc (9-fluorenylmethyloxycarbonyl) protection strategies are applicable and that peptide bonds may be formed using the various activation procedures known to the person skilled in the art, e.g., by reacting a C-terminal activated derivative (acid halide, acid anhydride, activated ester e.g., HObt-ester, etc.) of the appropriate amino acid or peptide with the amino group of the relevant amino acid or peptide as known to a person skilled in peptide chemistry. Furthermore, it may be necessary or desirable to include side-chain protection groups when using amino acid residues carrying functional groups which are reactive under the prevailing conditions. The necessary protection scheme will be known to the person skilled in the art (see e.g., M. Bodanszky and A. Bodanszky, "The Practice of Peptide Synthesis", 2. Ed, Springer- Verlag, 1994, J. Jones, "The Chemical Synthesis of Peptides", Clarendon Press, 1991, and Dryland et al., 1986, J. Chem. Soc, Perkin Trans. 1 :125-137). The peptide conjugates may also be prepared by means of recombinant DNA-technology using general methods and principles known to the person skilled in the art. A nucleic acid sequence encoding the conjugate may be prepared synthetically by established standard methods, e.g., the phosphoamidite method described by S.L. Beaucage and M.H. Caruthers, Tetrahedron Letters 22, 1981, pp. 1859-1869, or the method described by Matthes et al., EMBO Journal 3, 1984, pp. 801-805. According to the phosphoamidite method, oligonucleotides are synthesized, e.g., in an automatic DNA synthesizer, purified, annealed, ligated and cloned in suitable vectors. The techniques used to isolate or clone a nucleic acid sequence encoding the pharmacologically active peptide X are known in the art and include isolation from genomic DNA, preparation from cDNA, or a combination thereof. The cloning of the nucleic acid sequences of the present invention from such genomic DNA can be effected, e.g., by using the well known polymerase chain reaction (PCR) or antibody screening of expression libraries to detect cloned DNA fragments with shared structural features. See, e.g., Innis et al., 1990, A Guide to Methods and Application, Academic Press, New York. Other nucleic acid amplification procedures such as ligase chain reaction (LCR), ligated activated transcription (LAT) and nucleic acid sequence-based amplification (NASBA) may be used. It can then be ligated to a nucleic acid sequence encoding Z. The nucleic acid sequence encoding the conjugate is then inserted into a recombinant expression vector which may be any vector which may conveniently be subjected to recombinant DNA procedures. The choice of vector will often depend on the host cell into which it is to be introduced. Thus, the vector may be an autonomously replicating vector, i.e., a vector which exists as an extrachromosomal entity, the replication of which is independent of chromosomal replication, e.g., a plasmid. Alternatively, the vector may be one which, when introduced into a host cell, is integrated into the host cell genome and replicated together with the chromosome(s) into which it has been integrated. In the vector, the nucleic acid sequence encoding the conjugate of the present invention should be operably connected to a suitable promoter sequence. The promoter may be any nucleic acid sequence which shows transcriptional activity in the host cell of choice and may be derived from genes encoding proteins either homologous or heterologous to the host cell. Examples of suitable promoters for directing the transcription of the nucleic acid sequence encoding said conjugate in mammalian cells are the SV 40 promoter (Subramani et al., Mol. Cell Biol. 1, 1981, pp. 854-864), the MT-1 (metallothionein gene) promoter (Palmiter et al., Science 222, 1983, pp. 809-814) or the adenovirus 2 major late promoter, a Rous sarcoma virus (RSV) promoter, cytomegalovirus (CMV) promoter (Boshart et al., 1981, Cell 41 :521-530) and a bovine papilloma virus promoter (BPV). A suitable promoter for use in insect cells is the polyhedrin promoter (Vasuvedan et al., FEBS Lett. 311, 1992, pp. 7-11). Examples of suitable promoters for directing the transcription of the nucleic acid sequence encoding the conjugate, especially in a bacterial host cell, are the promoters obtained from the E. coli lac operon, the Streptomyces coelicolor agarase gene (dagA), the Bacillus subtilis levansucrase gene (sacB), the Bacillus licheniformis alpha-amylase gene (amyL), the Bacillus stearothermophilus maltogenic amylase gene (amyM), the Bacillus amyloliquefaciens alpha amylase gene (amyQ), the Bacillus licheniformis penicillinase gene (penP), the Bacillus subtilis xylA and xylB genes, and the prokaryotic beta-lactamase gene (Villa- Kamaroff et al., 1978, Proceedings of the National Academy of Sciences USA 75:3727-3731), as well as the tac promoter (DeBoer et al., 1983, Proceedings of the National Academy of Sciences USA 80:21 25). Further promoters are described in "Useful proteins from recombinant bacteria" in Scientific American, 1980, 242:74-94; and in Sambrook et al., 1989, supra. Examples of suitable promoters for directing the transcription of the nucleic acid sequence encoding the conjugate in a filamentous fungal host cell are promoters obtained from the genes encoding Aspergillus oryzae TAKA amylase, Rhizomucor miehei aspartic proteinase, Aspergillus niger neutral alpha-amylase, Aspergillus niger acid stable alpha-amylase, Aspergillus niger or Aspergillus awamori glucoamylase (glaA), Rhizomucor miehei lipase, Aspergillus oryzae alkaline protease, Aspergillus oryzae triose phosphate isomerase, Aspergillus nidulans acetamidase, Fusarium oxysporum trypsin-like protease (as described in U.S. Patent No. 4,288,627, which is incoφorated herein by reference), and hybrids thereof. Particularly preferred promoters for use in filamentous fungal host cells are the TAKA amylase, NA2-tpi (a hybrid of the promoters from the genes encoding Aspergillus niger neutral a amylase and Aspergillus oryzae triose phosphate isomerase), and glaA promoters. In a yeast host, useful promoters are obtained from the Saccharomyces cerevisiae enolase (ENO-1) gene, the Saccharomyces cerevisiae galactokinase gene (GAL1), the Saccharomyces cerevisiae alcohol dehydrogenase/glyceraldehyde-3-phosphate dehydrogenase genes (ADH2/GAP), and the Saccharomyces cerevisiae 3-phosphoglycerate kinase gene. Other useful promoters for yeast host cells are described by Romanos et al., 1992, Yeast 8:423-488. The nucleic acid sequence encoding said conjugate may also be operably connected to a suitable terminator, such as the human growth hormone terminator (Palmiter et al., op. cit.) Preferred terminators for filamentous fungal host cells are obtained from the genes encoding Aspergillus oryzae TAKA amylase, Aspergillus niger glucoamylase, Aspergillus nidulans anthranilate synthase, Aspergillus niger alpha-glucosidase, and Fusarium oxysporum trypsin-like protease. Preferred terminators for yeast host cells are obtained from the genes encoding Saccharomyces cerevisiae enolase, Saccharomyces cerevisiae cytochrome C (CYCl), or Saccharomyces cerevisiae glyceraldehyde-3-phosphate dehydrogenase. Other useful terminators for yeast host cells are described by Romanos et al., 1992, supra. The vector may further comprise elements such as polyadenylation signals (e.g., from SV 40 or the adenovirus 5 Elb region), transcriptional enhancer sequences (e.g., the SV 40 enhancer) and translational enhancer sequences (e.g., the ones encoding adenovirus VA RNAs). Furthermore, preferred polyadenylation sequences for filamentous fungal host cells are obtained from the genes encoding Aspergillus oryzae TAKA amylase, Aspergillus niger glucoamylase, Aspergillus nidulans anthranilate synthase, and Aspergillus niger alpha- glucosidase. Useful polyadenylation sequences for yeast host cells are described by Guo and Sherman, 1995, Molecular Cellular Biology 15:5983-5990. The recombinant expression vector may further comprise a DNA sequence enabling the vector to replicate in the host cell in question. Examples of such a sequence (when the host cell is a mammalian cell) is the SV 40 or polyoma origin of replication. Examples of bacterial origins of replication are the origins of replication of plasmids pBR322, pUC19, pACYC177, pACYC184, pUBl lO, pE194, pTA1060, and pAMBl . Examples of origin of replications for use in a yeast host cell are the 2 micron origin of replication, the combination of CEN6 and ARS4, and the combination of CEN3 and ARS 1. The origin of replication may be one having a mutation to make its function temperature-sensitive in the host cell (see, e.g., Ehrlich, 1978, Proc. Natl. Acad. Sci. USA 75:1433). The vector may also comprise a selectable marker, e.g., a gene the product of which complements a defect in the host cell, such as the gene coding for dihydrofolate reductase (DHFR) or one which confers resistance to a drug, e.g., neomycin, geneticin, ampicillin, or hygromycin. Suitable markers for yeast host cells are ADE2, HIS3, LEU2, LYS2, MET3, TRPl, and URA3. A selectable marker for use in a filamentous fungal host cell may be selected from the group including, but not limited to, amdS (acetamidase), argB (ornithine carbamoyltransferase), bar (phosphinothricin acetyltransferase), hygB (hygromycin phosphotransf erase), niaD (nitrate reductase), pyrG (orotidine-5' -phosphate decarboxylase), sC (sulfate adenyltransferase), tφC (anthranilate synthase), and glufosinate resistance markers, as well as equivalents from other species. Preferred for use in an Aspergillus cell are the amdS and pyrG markers of Aspergillus nidulans or Aspergillus oryzae and the bar marker of Streptomyces hygroscopicus. Furthermore, selection may be accomplished by cotransformation, e.g., as described in WO 91/17243, where the selectable marker is on a separate vector. The procedures used to ligate the nucleic acid sequences coding for the conjugate, the promoter and the terminator, respectively, and to insert them into suitable vectors containing the information necessary for replication, are well known to persons skilled in the art (cfi, for instance, Sambrook et al., op.cit.). The host cell into which the expression vector is introduced may be any cell which is capable of producing the conjugate and is may be a eukaryotic cell, such as invertebrate (insect) cells or vertebrate cells, e.g., Xenopus laevis oocytes or mammalian cells, in particular insect and mammalian cells. Examples of suitable mammalian cell lines are the COS (e.g., ATCC CRL 1650), BHK (e.g., ATCC CRL 1632, ATCC CCL 10) or CHO (e.g., ATCC CCL 61) cell lines. Methods for transfecting mammalian cells and expressing DNA sequences introduced in the cells are described in e.g., Kaufman and Shaφ, 1982, J. Mol. Biol. 159:601-621; Southern and Berg, 1982, J. Mol. Appl. Genet. 1:327-341; Loyter et al., 1982, Proc. Natl. Acad. Sci. USA 79:422-426; Wigler et al., 1978, Cell 14:725; Corsaro and Pearson, 1981, Somatic Cell Genetics 7:603, Graham and van der Eb, 1973, Virology 52:456; Fraley et al., 1980, JBC 225:10431; Capecchi, 1980, Cell 22:479; Wiberg et al., 1983,NAR 11 :7287; and Neumann et al., 1982, EMBO J. 1:841-845. The host cell may also be a unicellular pathogen, e.g., a prokaryote, or a non-unicellular pathogen, e.g., a eukaryote. Useful unicellular cells are bacterial cells such as gram positive bacteria including, but not limited to, a Bacillus cell, e.g., Bacillus alkalophilus, Bacillus amyloliquefaciens, Bacillus brevis, Bacillus circulans, Bacillus coagulans, Bacillus lautus, Bacillus lentus, Bacillus licheniformis, Bacillus megaterium, Bacillus stearothermophilus, Bacillus subtilis, and Bacillus thuringiensis; or a Streptomyces cell, e.g., Streptomyces lividans or Streptomyces murinus, or gram negative bacteria such as E. coli and Pseudomonas sp. The transformation of a bacterial host cell may, for instance, be effected by protoplast transformation (see, e.g., Chang and Cohen, 1979, Molecular General Genetics 168:1 1 1-1 15), by using competent cells (see, e.g., Young and Spizizin, 1961 , Journal of Bacteriology 81 :823-829, or Dubnar and Davidoff Abelson, 1971, Journal of Molecular Biology 56:209-221), by electroporation (see, e.g., Shigekawa and Dower, 1988, Biotechniques 6:742-751), or by conjugation (see, e.g., Koehler and Thorne, 1987, Journal of Bacteriology 169:5771-5278). The host cell may be a fungal cell. "Fungi" as used herein includes the phyla Ascomycota, Basidiomycota, Chytridiomycota, and Zygomycota (as defined by Hawksworth et al., In, Ainsworth and Bisby's Dictionary of The Fungi, 8th edition, 1995, CAB International, University Press, Cambridge, UK) as well as the Oomycota (as cited in Hawksworth et al., 1995, supra, page 171) and all mitosporic fungi (Hawksworth et al., 1995, supra). Representative groups of Ascomycota include, e.g., Neurospora, Eupenicillium (=Penicillium), Emericella (=Aspergillus), Eurotium (=Aspergillus), and the true yeasts listed above. The fungal host cell may also be a yeast cell. "Yeast" as used herein includes ascosporogenous yeast (Endomycetales), basidiosporogenous yeast, and yeast belonging to the Fungi Imperfecti (Blastomycetes). The medium used to culture the cells may be any conventional medium suitable for growing mammalian cells, such as a serum-containing or serum-free medium containing appropriate supplements, or a suitable medium for growing insect, yeast or fungal cells. Suitable media are available from commercial suppliers or may be prepared according to published recipes (e.g,. in catalogues of the American Type Culture Collection). The conjugate produced by the cells may then be recovered from the culture medium by conventional procedures including separating the host cells from the medium by centrifugation or filtration, precipitating the proteinaceous components of the supernatant or filtrate by means of a salt, e.g., ammonium sulphate, purification by a variety of chromatographic procedures, e.g., ion exchange chromatography, affinity chromatography, or the like. The invention is further illustrated by the following examples. EXAMPLES Peptide Synthesis General Procedures Apparatus and synthetic strategy Peptides were synthesized batchwise in a polyethylene vessel equipped with a polypropyle- ne filter for filtration using 9-fluorenylmethyloxycarbonyl (Fmoc) as the N-α-amino protecting group and suitable common protection groups for side-chain functionalities (Dryland et al., 1986, J. Chem. Soc, Perkin Trans. 1 :125-137). Solvents Solvent DMF (N,N-dimethylformamide, Riedel de-Haen, Germany) was purified by passing it through a column packed with a strong cation exchange resin (Lewatit S 100 MB/H strong acid, Bayer AG Leverkusen, Germany) and analysed for free amines prior to use by addition of 3,4-dihydro-3-hydroxy-4-oxo-l,2,3-benzotriazine (Dhbt-OH) giving rise to a yellow colour (Dhbt-O-anion) if free amines are present. Solvent DCM (dichloromethane, analytical grade, Riedel de-Haen, Germany) was used directly without purification. Amino acids Fmoc-protected amino acids were purchased from MilliGen (UK) and from PerSeptive Biosystems GmbH Hamburg, Germany in suitable side-chain protected forms. Νon-protein amino acids FmocOrn(Boc)-OH, Fmoc-2-D-Νal-OH, Fmoc-D-Phe-OH, Fmoc-Aib-OH were purchased from Bachem (Switzerland) and FmocDbu(Boc)-OH, FmocDpr(Boc)-OH from Neosystem, France. Linker (4-hydroxymethylphenoxy)acetic acid (HMPA), Novabiochem, Switzerland was coupled to the resin either as a preformed or in situ generated 1 -hydroxybenzotriazole (HObt) ester by means of DIC. Coupling reagents Coupling reagent diisopropylcarbodiimide (DIC) was purchased from (Riedel de-Haen, Germany) and distilled prior to use, dicyclohexylcarbodiimide (DCC) was purchased from Merck-Schuchardt, Munchen, Germany, and purified by distillation. Solid supports Peptides synthesized according to the Fmoc-strategy were synthesized on the following types of solid support using 0.05 M or higher concentrations of Fmoc-protected activated amino acid in DMF. 1) PEG-PS (polyethyleneglycol grafted on polystyrene; 2) NovaSyn TG resin, 0.29 mmol/g, Novabiochem, Switzerland); 3) TentaGel S resins 0.22-0.31 mmol/g (TentaGel-S-NH2; TentaGel S-Ram, TentaGel S PHB-Lys(Boc)Fmoc, TentaGel S RAM-Lys(Boc)Fmoc; Rapp polymere, Germany). Catalysts and other reagents Diisopropylethylamine (DIEA) was purchased from Aldrich, Germany, and ethylenediami- ne from Fluka, piperidine and pyridine from Riedel-de Haen, Frankfurt, Germany. 4-(N,N- dimethylamino)pyridine (DMAP) was purchased from Fluka, Switzerland and used as a catalyst in coupling reactions involving symmetrical anhydrides. Ethanedithiol was purchased from Riedel-de Haen, Frankfurt, Germany. 3,4-dihydro-3-hydroxy-4-oxo-l,2,3- benzotriazine (Dhbt-OH) and 1 -hydroxybenzotriazole (HObt) were obtained from Fluka, Switzerland. Enzymes Carboxypeptidase A (EC 3.4.17.1) type I from bovine pancreas, leucine aminopeptidase (EC 3.4.11.1) type III-CP from porcine kidney, α-chymotrypsin (EC 4.4.21.1) from bovine pancreas, and pepsin A (EC 3.4.23.1) from porcine stomach mucosa bovine pancreas were obtained from Sigma, UK. Coupling procedures The first amino acid was coupled as a symmetrical anhydride in DMF generated from the appropriate N-α-protected amino acid by means of DIC or DCC. The following amino acids were coupled as preformed HObt esters made from appropriate N-α-protected amino acids and HObt by means of DIC in DMF. Acylations were checked by the ninhydrin test performed at 80°C in order to prevent Fmoc deprotection during the test (Larsen, B. D. and Holm, A., 1994, Int. J. Peptide Protein Res. 43:1-9). Coupling as HObt-ester Method a. 3 eq. N-α-amino protected amino acid was dissolved in DMF together with 3 eq. HObt and 3 eq DIC. The solution was left at r.t. for 10 minutes and then added to the resin, which had been washed with a solution of 0.2% Dhbt-OH in DMF prior to the addition of the preactivated amino acid. Method b. 3 eq. N-α-amino protected amino acid was dissolved in DMF together with 3 eq. HObt. 3 eq DIC were added just prior to use. The final solution was added to the resin. Preformed symmetrical anhydride 6 eq. N-α-amino protected amino acid was dissolved in DCM and cooled to 0°C. DCC or DIC (3 eq.) was added and the reaction continued for 10 min. The solvent was removed in vacuo and the residue dissolved in DMF. The DMF-solution was filtered in case of using DCC and immediately added to the resin followed by 0.1 eq. of DMAP. Estimation of the coupling yield of the first N-α-amino protected amino acid 3-5 mg dry Fmoc-protected pepti de-resin was treated with 5 ml 20% piperidine in DMF for 10 min at r.t. and the UV absoφtion for the dibenzofulvene-piperidine adduct was estimated at 301 nm. The yield was determined using a calculated etinction coefficient ε 30 ι based on a Fmoc-Ala-OH standard. Deprotection of the N-α-amino Fmoc protecting group Deprotection of the Fmoc group was performed by treatment with 20% piperidine in DMF (1 x 5 and 1 x 10 min.), followed by wash with DMF until no yellow colour (Dhbt-O-) could be detected after addition of Dhbt-OH to the drained DMF. Cleavage of peptide from resin with acid Method a. Peptides were cleaved from the resins by treatment with 95%> trifluoroacetic acid (TFA, Riedel-de Haen, Frankfurt, Germany)-water v/v or with 95% TFA and 5% ethanedithiol v/v at r.t. for 2 h. The filtered resins were washed with 95% TFA-water and filtrates and washings evaporated under reduced pressure. The residue was washed with ether and freeze dried from acetic acid-water. The crude freeze dried product was analysed by high-performance liquid chromatography (HPLC) and identified by mass spectrometry (MS). Method b. Peptides were cleaved from the resins by treatment with 95% trifluoroacetic acid (TFA, Riedel-de Haen, Frankfurt, Germany)-water v/v or with 95% TFA and 5% ethanedithiol v/v at r.t. for 2 h. The filtered resins were washed with 95% TFA-water and filtrates and washings were diluted by adding 10%> acetic acid. The resulting mixture was extracted 3 times with ether and finally freeze dried. The crude freeze dried product was analysed by high-performance liquid chromatography (HPLC) and identified by mass spectrometry (MS). Method c. Peptides were cleaved from the resins by treatment with 95% trifluoroacetic acid and 5% triisopropylsilane (Sigma) v/v at r.t. for 2 h. The filtered resins were washed with 95%> TFA-water and filtrates and washings evaporated under reduced pressure. The residue was washed with ether and freeze dried from acetic acid-water. The crude freeze dried product was analysed by high-performance liquid chromatography (HPLC) and identified by mass spectrometry (MS). Disulfide bond formation The crude Acm protected peptide was dissolved in methanol/water 4:1 and pH adjusted to 3.33 (by adding cone. Acetic acid) and the concentration of the peptide was approximately 10 ~ 3 M. 10-eq iodine dissolved in methanol (20 mg/ml) was added to the peptide solution in one portion. The reaction proceeded for 4-5 days at -18 to -20°C and was followed by HPLC. The reaction mixture was then diluted by adding one extra volume water, and extracted 3 times with chloroform or tetrachlormethane. The clear water solution was then freeze-dried and the product was purified by preparative HPLC as described above. Batchwise peptide synthesis on PEG-PS NovaSyn TG resin (250 mg, 0.27-0.29 mmol/g) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration. The resin was swelled in DMF (5 ml), and treated with 20%> piperidine in DMF to secure the presence of non-protonated amino groups on the resin. The resin was drained and washed with DMF until no yellow colour could be detected after addition of Dhbt-OH to the drained DMF. HMPA (3 eq.) was coupled as a preformed HObt-ester as described above and the coupling was continued for 24 h. The resin was drained and washed with DMF (5 x 5 ml, 5 min each) and the acylation checked by the ninhydrin test. The first amino acid was coupled as a preformed symmetrical anhydride as described above. The coupling yields of the first Fmoc-protected amino acids were estimated as described above. It was in all cases better than 60%. The following amino acids according to the sequence were coupled as preformed Fmoc-protected, and if necessary side-chain protected, HObt esters (3 eq.) as described above. The couplings were continued for 3 h, unless otherwise specified. The resin was drained and washed with DMF (5 x 5 ml, 5 min each) in order to remove excess reagent. All acylations were checked by the ninhydrin test performed at 80°C. After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 5 min each), DCM (3x5 ml, 1 min each) and finally diethyl ether (3x5 ml, 1 min each) and dried in vacuo over night. Batchwise peptide synthesis on TentaGel S-NH2 TentaGel S-NH2 resin (100-500 mg, 0.22-0.31 mmol/g) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration. The resin was swelled in DMF (5-10 ml), and treated with 20% piperidine in DMF to secure the presence of non-protonated amino groups on the resin. The resin was drained and washed with DMF until no yellow colour could be detected after addition of Dhbt-OH to the drained DMF. HMPA (3 eq.) was coupled as an HObt-ester generated in situ by means of DIC as described above and the coupling was continued for 24 h. The resin was drained and washed with DMF (4 x 5-10 ml, 2 min each) and the acylation checked by the ninhydrin test. The first amino acid was coupled as a preformed symmetrical anhydride as described above. The coupling yields of the first Fmoc-protected amino acids were estimated as described above. It was in all cases better than 60%. The following amino acids according to the sequence were coupled as Fmoc-protected HObt esters (3 eq.) generated in situ by means of DIC as described above. The couplings were continued for 3 h, unless otherwise specified. The resin was drained and washed with DMF (4 x 5-10 ml, 2 min each) in order to remove excess reagent. All acylations were checked by the ninhydrin test performed at 80 °C. After completion of the synthesis, the peptide-resin was washed with DMF (3 x 5-10 ml, 5 min each), DCM (3 x 5- 10 ml, 1 min each) and finally diethyl ether (3 x 5-10 ml, 1 min each) and dried in vacuo. Batchwise peptide synthesis on TentaGel S-RAM TentaGel S-RAM resin (100-1000 mg, 0.22-0.31 mmol/g) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration. The resin was swelled in DMF (5- 10 ml), and the Fmoc group was removed according to the procedure described above. The following amino acids according to the sequence were coupled as Fmoc-protected HObt esters (3 eq.) generated in situ by means of DIC as described above. The couplings were continued for 3 h, unless otherwise specified. The resin was drained and washed with DMF (4 x 5-10 ml, 2 min each) in order to remove excess reagent. All acylations were checked by the ninhydrin test performed at 80°C. After completion of the synthesis, the peptide-resin was washed with DMF (3 x 5-10 ml, 5 min each), DCM (3 x 5-10 ml, 1 min each) and finally diethyl ether (3 x 5-10 ml, 1 min each) and dried in vacuo. HPLC conditions Isocratic HPLC analysis was preformed on a Shimadzu system consisting of an LC-6A pump, an MERCK HITACHI L-4000 UV detector operated at 215 nm and a Rheodyne 7125 injection valve with a 20 μl loop. The column used for isocratic analysis was a Spherisorb ODS-2 (100 x 3 mm; 5-μm particles) (MicroLab, Aarhus, Denmark). HPLC analysis using gradients was performed on a MERCK-HITACHI L-6200 Intelligent pump, an MERCK HITACHI L-4000 UV detector operated at 215 nm and a Rheodyne 7125 injection valve with a 20 μl loop, or on a Waters 600 E instrument equipped with a Waters 996 photodiode array detector. The columns used were a RescorceTM R C 1 ml (Waters) or a LiChroCART 125-4, LiChrospher 100 RP-18 (5 μm) (Merck). Buffer A was 0.1 vol % TFA in water and buffer B 90 vol% acetonitrile, 9.9 vol% water and 0.1 vol% TFA. The buffers were pumped through the columns at a flow rate of 1.3-1.5 ml/min using either of the following gradients for peptide analysis 1) Linear gradient from 0% - 100% B (30 min) or 2) 0% B (2 min) linear gradient from 0-50% B (23 min) 50-100% B (5 min). For Preparative HPLC, purification was performed on a Waters 600 E instrument equipped with a Waters 996 photodiode array detector. The column used was a Waters Delta-Pak C- 18 15 μm, 100 A, 25 x 100 mm. Gradient "2)" was used with a flow rate of 9 ml/min. Mass spectroscopy Mass spectra were obtained on a Finnigan Mat LCQ instrument equipped with an electrospray (ESI) probe (ES-MS) and on a TofSpec E, Fisons Instrument (MALDI-TOF) using β-cyano-p-hydroxycinnamic acid as matrix. Peptide synthesis of individual peptides 1. Peptide synthesis of H-Tyr-Gly-Gly-Phe-Leu-Glu -OH (Leu-enkephalin-Glu -OH) on NovaSyn TentaGel Dry NovaSyn TG resin (0.29 mmol/g, 250 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and treated as described under "batchwise peptide synthesis on PEG-PS" until finishing the peptide probe Glιi 6 . The following amino acids forming the Leu-enkephalin sequence were coupled as preformed Fmoc-protected, if necessary side-chain protected, HObt esters (3 eq.) in DMF (5 ml) generated by means of DIC. Before each of the last five couplings, the resin was washed with a solution of Dhbt- OH (80 mg in 25 ml), in order to follow the disappearance of the yellow colour as the coupling reaction proceeded. When the yellow colour was no longer visible, the couplings were interrupted by washing the resin with DMF (5 x 5 ml, 5 min each). The acylations were then checked by the ninhydrin test performed at 80°C as earlier described. After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method a. The crude freeze dried product was analysed by HPLC and the purity was found to be better than 90%. The identity of the peptide was confirmed by ES-MS. Yield 76%>. 2. Peptide synthesis of H-Tyr-Gly-Gly-Phe-Leu-Lys -OH (Leu-enkephaIin-Lys -OH) on NovaSyn TentaGel Dry NovaSyn TG resin (0.29 mmol/g, 250 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and treated as described under "batchwise peptide synthesis on PEG-PS" until finishing the peptide probe Lys . The following amino acids forming the Leu-enkephalin sequence were coupled as preformed Fmoc-protected HObt esters (3 eq.) in DMF (5 ml) generated by means of DIC. Before each of the last five couplings, the resin was washed with a solution of Dhbt-OH (80 mg in 25 ml), in order to follow the disappearance of the yellow colour as the coupling reaction proceed. When the yellow colour was no longer visible, the couplings were interrupted by washing the resin with DMF (5 x 5 ml, 5 min each). The acylations were then checked by the ninhydrin test performed at 80°C as earlier described. After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method a. The crude freeze dried product was analysed by HPLC and the purity was found to be better than 98%. The identity of the peptide was confirmed by ES-MS. Yield 84%. 3. Peptide synthesis of H-Lys 6 -Tyr-Gly-Gly-Phe-Leu-OH (H-Lys -Leu-enkephalin) on NovaSyn TentaGel Dry NovaSyn TG resin (0.29 mmol/g, 250 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and treated as described under "batchwise peptide synthesis on PEG-PS" and the first amino acid leucine was coupled as described under coupling procedures. The following amino acids forming the H-Lys,-enkephalin sequence were coupled as preformed Fmoc-protected HObt esters (3 eq.) in DMF (5 ml) generated by means of DIC and the couplings were continued for at least 2 hours. The acylations were then checked by the ninhydrin test performed at 80°C as earlier described. After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin as described above using 95% TFA and 5%> water (v/v) as cleavage reagent and freeze dried from acetic acid. The crude freeze dried product was analysed by HPLC and found to be homogeneous without deletion and Fmoc-protected sequences. The purity was found to be better than 98% and the identity of the peptide conjugate was confirmed by ES-MS. Yield 89%>. 4. Peptide synthesis of H-Lys 6 -Tyr-Gly-Gly-Phe-Leu-Lys 6 -OH (H-Lys 6 -Leu-enkephalin- Lys -OH) on NovaSyn TentaGel Dry NovaSyn TG resin (0.29 mmol/g, 250 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and treated as described under "batchwise peptide synthesis on PEG-PS" until finishing the peptide probe Lys fi . The following amino acids forming the H-Lys 6 -enkephalin sequence were coupled as preformed Fmoc-protected HObt esters (3 eq.) in DMF (5 ml) generated by means of DIC and the couplings were continued for at least 2 hours. The acylations were then checked by the ninhydrin test performed at 80°C as earlier described. After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method a. The crude freeze dried product was analysed by HPLC and the purity was found to be better than 98%. The identity of the peptide was confirmed by ES-MS. Yield 90%. 5. Peptide synthesis of H-Tyr-Gly-Gly-Phe-Leu-Lys-Lys-Glu-Glu-Glu-Lys— OH (Leu- enkephalin-Lys-Lys-Glu-Glu-Glu-Lys-OH) on TentaGel S-PHB-Lys(Boc)Fmoc Dry TentaGel S-PHB-Lys(Boc)Fmoc resin (0.22 mmol/g, 500 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and swelled for two hours in DMF (5 ml). The Fmoc group on the first lysine was removed as described above and the synthesis was continued until finishing the peptide sequence as described under "Batchwise peptide synthesis on TentaGel S-PHB-Lys(Boc)Fmoc". After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method b as described above and freeze dried from acetic acid. The crude freeze dried peptide was purified by preparative HPLC using the procedure described above. The purified product was found to be homogeneous and the purity was found to be better than 90%. The identity of the peptide was confirmed by ES-MS. Yield 60 %. 6. Peptide synthesis of H-Tyr-Gly-Gly-Phe-Leu-Lys-Glu-Glu-Glu-Glu-Lys-OH (Leu- enkephalin-Lys-Glu-Glu-Glu-Glu-Lys-OH) on TentaGel S-PHB-Lys(Boc)Fmoc Dry TentaGel S-PHB-Lys(Boc)Fmoc resin (0.22 mmol/g, 500 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and swelled for two hours in DMF (5 ml). The Fmoc group on the first lysine was removed as described above. And the synthesis was continued until finishing the peptide sequence as described under "Batchwise peptide synthesis on TentaGel S-PHB-Lys(Boc)Fmoc". After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method b as described above and freeze dried from acetic acid. The crude freeze dried peptide was purified by preparative HPLC using the procedure described above. The purified product was found to be homogeneous and the purity was found to be better than 98%. The identity of the peptide was confirmed by ES-MS. Yield 65%. 7. Peptide synthesis of H-Tyr-Gly-Gly-Phe-Leu-(Orn)6-OH (Leu-enkephalin-(Orn)6-OH) on TentaGel S-NH2 Dry TentaGel S-NH2 resin (0.31 mmol/g, 500 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and swelled for two hours in DMF (5 ml). The peptide according to the sequence was assembled as described under "Batchwise peptide synthesis on TentaGel S resins". After completion of the synthesis, the peptide- resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method b as described above and freeze dried from acetic acid. The crude freeze dried product was oxidized in order to make the disulfide bond according to the procedure described above. The crude cyclized peptide was purified by preparative HPLC using the procedure described above. The purified product was found to be homogeneous and the purity was found to be better than 90%. The identity of the peptide was confirmed by ES-MS. Yield 20%>. 8. Peptide synthesis of H-Tyr-Gly-Gly-Phe-Leu-(Dbu)6-OH (Leu-enkephalin-(Dbu)6-OH) on TentaGel S-NHg Dry TentaGel S-NH2 resin (0.31 mmol/g, 500 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and swelled for two hours in DMF (5 ml). The peptide according to the sequence was assembled as described under "Batchwise peptide synthesis on TentaGel S resins". After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method b as described above and freeze dried from acetic acid. The crude freeze dried product was oxidized in order to make the disulfide bond according to the procedure described above. The crude cyclized peptide was purified by preparative HPLC using the procedure described above. The purified product was found to be homogeneous and the purity was found to be better than 90%. The identity of the peptide was confirmed by ES-MS. Yield 22%. 9. Peptide synthesis of H-Tyr-Gly-Gly-Phe-Leu-(Dpr)6-OH (Leu-enkephalin-(Dpr)6-OH) on TentaGel S-NH2 Dry TentaGel S-NH2 resin (0.31 mmol/g, 500 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and swelled for two hours in DMF (5 ml). The peptide according to the sequence was assembled as described under "Batchwise peptide synthesis on TentaGel S resins". After completion of the synthesis, the peptide- resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method b as described above and freeze dried from acetic acid. The crude peptide was purified by preparative HPLC using the procedure described above. The purified product was found to be homogeneous and the purity was found to be better than 98%. The identity of the peptide was confirmed by ES- MS. Yield 22%. 10. Peptide synthesis of H-Tyr-Gly-Gly-Phe-Leu-LysiQ-OH (Leu-enkephalin-LysiQ-OH) on TentaGel S-PHB-Lys(Boc)Fmoc Dry TentaGel S-PHB-Lys(Boc)Fmoc resin (0.22 mmol/g, 500 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and swelled for two hours in DMF (5 ml). The Fmoc group on the first lysine was removed as described above and the synthesis was continued until finishing the peptide sequence as described under "Batchwise peptide synthesis on TentaGel S-PHB-Lys(Boc)Fmoc". After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method b as described above and freeze dried from acetic acid. The crude freeze dried peptide was purified by preparative HPLC using the procedure described above. The purified product was found to be homogeneous and the purity was found to be better than 98%. The identity of the peptide was confirmed by ES-MS. Yield 7.1%. 11. Peptide synthesis of H-Tφ-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu-Glup-OH (DSIP-Glu 6 - OH) on NovaSyn TentaGel Dry NovaSyn TG resin (0.29 mmol/g, 250 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and treated as described under "batchwise peptide synthesis on PEG-PS" until finishing the peptide probe Glu 6 . The following amino acids forming the DSIP sequence were coupled as preformed Fmoc-protected HObt esters (3 eq.) in DMF (5 ml) generated by means of DIC. Before each of the last nine couplings, the resin was washed with a solution of Dhbt-OH (80 mg in 25 ml), in order to follow the disappearance of the yellow colour as the coupling reaction proceeds. When the yellow colour was no longer visible, the couplings were interrupted by washing the resin with DMF (5 x 5 ml, 5 min each). The acylations were then checked by the ninhydrin test performed at 80°C as earlier described. After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each), and dried in vacuo. The peptide was cleaved from the resin according to method a. The crude freeze dried product was analysed by HPLC and the purity was found to be better than 98%. The identity of the peptide was confirmed by ES-MS. Yield 80%. 12. Peptide synthesis of H-Tφ-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu-(Lys-Glu) 3 -OH (DSIP- (Lys-Glu) 3 -OH) on NovaSyn TentaGel Dry NovaSyn TG resin (0.29 mmol/g, 250 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and treated as described under "batchwise peptide synthesis on PEG-PS" until finishing the peptide probe (LysGlu) 3 . The following amino acids forming the DSIP sequence were coupled as preformed Fmoc-protected HObt esters (3 eq.) in DMF (5 ml) generated by means of DIC. Before each of the last nine couplings, the resin was washed with a solution of Dhbt-OH (80 mg in 25 ml), in order to follow the disappearance of the yellow colour as the coupling reaction proceeds. When the yellow colour was no longer visible, the couplings were interrupted by washing the resin with DMF (5 x 5 ml, 5 min each). The acylations were then checked by the ninhydrin test performed at 80°C as earlier described. After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each), and dried in vacuo. The peptide was cleaved from the resin according to method a. The crude freeze dried product was analysed by HPLC and the purity was found to be better than 98%. The the identity of the peptide was confirmed by ES-MS. Yield 91%. 13. Peptide synthesis of H-Tφ-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu-OH (DSIP) on NovaSyn TentaGel (Reference) Dry NovaSyn TG resin (0.29 mmol/g, 250 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and treated as described under "batchwise peptide synthesis on PEG-PS". The first amino acid was coupled as a preformed symmetrical anhydride as described above. The coupling yields of the first Fmoc-protected amino acids were estimated as described above. The yields were in all cases better than 60%. The following amino acids forming the DSIP sequence were coupled as preformed Fmoc-protected HObt esters (3 eq.) in DMF (5 ml) generated by means of DIC. Before each of the last eight couplings, the resin was washed with a solution of Dhbt-OH (80 mg in 25 ml), in order to follow the disappearance of the yellow colour as the coupling reaction proceeds. When the yellow colour was no longer visible, the couplings were interrupted by washing the resin with DMF (5 x 5 ml, 5 min each). The acylations were then checked by the ninhydrin test performed at 80°C as earlier described. After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each), and dried in vacuo. The peptide was cleaved from the resin according to method a. The crude freeze dried product was analysed by HPLC and the purity was found to be better than 98%). The the identity of the peptide was confirmed by ES-MS. Yield 78%. 14. Peptide synthesis of H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-Lys 6 -OH (Substance P-Lys 6 -OH) on NovaSyn TentaGel Dry NovaSyn TG resin (0.29 mmol/g, 250 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and treated as described under "batchwise peptide synthesis on PEG-PS" until finishing the peptide probe Lys fi . The following amino acids forming the Substance P sequence were coupled as preformed Fmoc-protected HObt esters (3 eq.) in DMF (5 ml) generated by means of DIC and the couplings were continued for at least 2 hours. The acylations were then checked by the ninhydrin test performed at 80°C as earlier described. After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method a. The crude freeze dried product was analysed by HPLC and the purity was found to be better than 98%>. The identity of the peptide was confirmed by ES-MS. Yield 80%. 15. Peptide synthesis of H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (Substance-P-NH2) on TentaGel S-RAM Dry TentaGel S-RAM resin (0.25 mmol/g, 500 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and swelled for two hours in DMF (5 ml). The Fmoc group was removed according to the procedure described above, and the peptide according to the sequence was assembled as described under "Batchwise peptide synthesis on TentaGel S-RAM resins". After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method b as described above and freeze dried from acetic acid. The crude peptide was purified by preparative HPLC using the procedure described above. The purified product was found to be homogeneous and the purity was found to be better than 98%. The identity of the peptide was confirmed by ES- MS. Yield 12.3%. 16. Peptide synthesis of H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-Lys6-NH2 (Substance-P-Lys6-NH2) on TentaGel S-RAM-Lys(Boc)Fmoc Dry TentaGel S-RAM-Lys(Boc)Fmoc resin (0.22 mmol/g, 500 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and swelled for two hours in DMF (5 ml). The Fmoc group on the first lysine was removed as described above and the synthesis was continued until finishing the peptide sequence as described under "Batchwise peptide synthesis on TentaGel S-Ram-Lys(Boc)Fmoc". After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method b as described above and freeze dried from acetic acid. The crude freeze dried product was purified by preparative HPLC using the procedure described above. The purified product was found to be homogeneous and the purity was found to be better than 98%. The identity of the peptide was confirmed by ES-MS. Yield 17.2%. 17. Peptide synthesis of H-(Lys) 6 -Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (K 6 -Substance-P-NH2) on TentaGel S-RAM Dry TentaGel S-RAM resin (0.25 mmol/g, 500 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and swelled for two hours in DMF (5 ml). The Fmoc group was removed according to the procedure described above, and the peptide according to the sequence was assembled as described under "Batchwise peptide synthesis on TentaGel S-RAM resins". After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method b as described above and freeze dried from acetic acid. The crude peptide was purified by preparative HPLC using the procedure described above. The purified product was found to be homogeneous and the purity was found to be better than 98%). The identity of the peptide was confirmed by ES- MS. Yield 10.3%. 18. Peptide synthesis of H-Aib-His-2-D-Nal-D-Phe-Lys-(Lys)6-NH2 (GHRP-(Lys)6-NH2) on TentaGel S-RAM-Lys(Boc)Fmoc Dry TentaGel S-RAM-Lys(Boc)Fmoc resin (0.22 mmol/g, 500 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and swelled for two hours in DMF (5 ml). The Fmoc group on the first lysine was removed as described above and the synthesis was continued until finishing the peptide sequence as described under "Batchwise peptide synthesis on TentaGel S-Ram-Lys(Boc)Fmoc". After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method b as described above and freeze dried from acetic acid. The crude freeze dried product was purified by preparative HPLC using the procedure described above. The purified product was found to be homogeneous and the purity was found to be better than 90%. The identity of the peptide was confirmed by ES-MS. Yield 35%. 19. Peptide synthesis of H-Aib-His-2-D-Nal-D-Phe-Lys-NH2 (GHRP-NHg) on TentaGel S- RAM Dry TentaGel S-RAM resin (0.25 mmol/g, 500 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and swelled for two hours in DMF (5 ml). The Fmoc group was removed according to the procedure described above, and the peptide according to the sequence was assembled as described under "Batchwise peptide synthesis on TentaGel S-RAM resins". After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method b as described above and freeze dried from acetic acid. The crude freeze dried product was found to be homogeneous and the purity was found to be better than 95%. The identity of the peptide was confirmed by ES-MS. Yield 21%. 20. Peptide synthesis of H-(Lys) 6 -Aib-His-2-D-Nal-D-Phe-Lys-NH2 (K 6 -GHRP-NH2) on TentaGel S-RAM Dry TentaGel S-RAM resin (0.25 mmol/g, 500 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and swelled for two hours in DMF (5 ml). The Fmoc group was removed according to the procedure described above, and the peptide according to the sequence was assembled as described under "Batchwise peptide synthesis on TentaGel S-RAM resins". After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method b as described above and freeze dried from acetic acid. The crude freeze dried product was found to be homogeneous and the purity was found to be better than 95%. The identity of the peptide was confirmed by ES-MS. Yield 19%. 21. Peptide synthesis of Glu-His-Tφ-Ser-Tyr-GIy-Leu-Arg-Pro-Gly-Lys 6 -OH (GnRH-Lys 6 - OH) on NovaSyn TentaGel Dry NovaSyn TG resin (0.29 mmol/g, 250 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and treated as described under "batchwise peptide synthesis on PEG-PS" until finishing the peptide probe Lys 6 . The following amino acids forming the GnRH sequence were coupled as preformed Fmoc-protected HObt esters (3 eq.) in DMF (5 ml) generated by means of DIC and the couplings were continued for at least 2 hours. The acylations were then checked by the ninhydrin test performed at 80°C as earlier described. After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method c. The crude freeze dried product was analysed by HPLC and it was found to contain the target peptide together with some impurities. The crude product was purified by preparative reverse-phase HPLC. The purity was found to be better than 98% and the identity of the peptide conjugate was confirmed by ES-MS. Yield 37%. 22. Peptide synthesis of pGlu-His-Tφ-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-(Lys-Glu) 3 -OH (GnRH-(Lys-Glu) 3 -OH) on NovaSyn TentaGel Dry NovaSyn TG resin (0.29 mmol/g, 250 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and treated as described under "batchwise peptide synthesis on PEG-PS" until finishing the peptide probe (Lys-Glu) 3 . The following amino acids forming the GnRH sequence were coupled as preformed Fmoc-protected HObt esters (3 eq.) in DMF (5 ml) generated by means of DIC and the couplings were continued for at least 2 hours. The acylations were then checked by the ninhydrin test performed at 80°C as earlier described. After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method c. The crude freeze dried product was analysed by HPLC and it was found to contain the target peptide together with some impurities. The crude product was purified by preparative reverse-phase HPLC. The purity was found to be better than 98% and the identity of the peptide conjugate was confirmed by ES-MS. Yield 43%. 23. Peptide synthesis of pGlu-His-Tφ-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH 2 (GnRH-NH 2 ) NH2 on TentaGel S-RAM. Dry TentaGel S-RAM resin (0.25 mmol/g, 500 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and swelled for two hours in DMF (5 ml). The Fmoc group was removed according to the procedure described above, and the peptide according to the sequence was assembled as described under "Batchwise peptide synthesis on TentaGel S-RAM resins". After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method b as described above and freeze dried from acetic acid. The crude freeze dried product was found to be homogeneous and the purity was found to be better than 95%. The identity of the peptide was confirmed by ES-MS. Yield 28%. 24. Peptide synthesis of H-(Lys) 6 -Gln-His-Tφ-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH 2 (K 6 - GnRH-NH 2 ) NHg on TentaGel S-RAM. Dry TentaGel S-RAM resin (0.25 mmol/g, 500 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and swelled for two hours in DMF (5 ml). The Fmoc group was removed according to the procedure described above, and the peptide according to the sequence was assembled as described under "Batchwise peptide synthesis on TentaGel S-RAM resins". After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method b as described above and freeze dried from acetic acid. The crude freeze dried product was found to be homogeneous and the purity was found to be better than 95%>. The identity of the peptide was confirmed by ES-MS. Yield 20%. 25. Peptide synthesis of H-Gly-Gly-Thr-Tyr-Ser-Cys-His-Phe-Gly-Pro-Leu-Thr-Tφ-Val- Cys-Lys-Pro-Gln-Gly-Gly-OH (EMP-1 -OH) on TentaGel S-NHg. Dry TentaGel S-NH2 resin (0.31 mmol/g, 500 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and swelled for two hours in DMF (5 ml). The peptide according to the sequence was assembled as described under "Batchwise peptide synthesis on TentaGel S resins". After completion of the synthesis, the peptide- resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method b as described above and freeze dried from acetic acid. The crude freeze dried product was oxidized without further purification, in order to make the disulfide bond according to the procedure described above. The crude cyclized peptide was purified by preparative HPLC using the procedure described above. The purified product was found to be homogeneous and the purity was found to be better than 98%. The identity of the peptide was confirmed by ES-MS. Yield 22%. 26. Peptide synthesis of H-Gly-Gly-Thr-Tyr-Ser-Cys-His-Phe-Gly-Pro-Leu-Thr-Tφ-Val- Cys-Lys-Pro-Gln-Gly-Gly-Lys6-OH (EMP-1 -LysfrOH) on TentaGel S-PHB- Lys(Boc)Fmoc Dry TentaGel S-PHB-Lys(Boc)Fmoc resin (0.22 mmol/g, 500 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and swelled for two hours in DMF (5 ml). The Fmoc group on the first lysine was removed as described above and the synthesis was continued until finishing the peptide sequence as described under "Batchwise peptide synthesis on TentaGel S-PHB-Lys(Boc)Fmoc". After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. 5 The peptide was cleaved from the resin according to method b as described above and freeze dried from acetic acid. The crude freeze-dried product was oxidised without further purification in order to make the disulphide bond according to the procedure described above. The crude cyclized peptide was purified by preparative HPLC using the procedure described above. The purified product was found to be homogeneous and the purity was 10 found to be better than 98%. The identity of the peptide was confirmed by ES-MS. Yield 27%. 27. Peptide synthesis of H-(Lys) 6 -Gly-Gly-Thr-Tyr-Ser-Cys-His-Phe-Gly-Pro-Leu-Thr-Tφ- Val-c7s-Lys-Pro-Gln-Gly-Gly-OH (K 6 -EMP-l-OH) on TentaGel S-NHg. 15 Dry TentaGel S-NH2 resin (0.31 mmol/g, 500 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and swelled for two hours in DMF (5 ml). The peptide according to the sequence was assembled as described under "Batchwise peptide synthesis on TentaGel S resins". After completion of the synthesis, the peptide- resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether 20 (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method b as described above and freeze dried from acetic acid. The crude freeze dried product was oxidized without further purification, in order to make the disulfide bond according to the procedure described 25 above. The crude cyclized peptide was purified by preparative HPLC using the procedure described above. The purified product was found to be homogeneous and the purity was found to be better than 98%. The identity of the peptide was confirmed by ES-MS. Yield 12%. 30 28. Peptide synthesis of H-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu- Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Tφ-Leu- Val-Lys-Gly- Arg-OH (GLP- 1 -(7- 36)(Human)-OH) on TentaGel S-NHg Dry TentaGel S-NH2 resin (0.31 mmol/g, 500 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and swelled for two hours in DMF (5 ml). The peptide according to the sequence was assembled as described under "Batchwise peptide synthesis on TentaGel S resins". After completion of the synthesis, the peptide- resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method b as described above and freeze dried from acetic acid. The crude freeze dried peptide was purified twice by preparative HPLC using the procedure described above. The purified product was found to be homogeneous and the purity was found to be better than 98%. The identity of the peptide was confirmed by ES-MS. Yield 8.7%. 29. Peptide synthesis of H-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu- Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile- Ala-Tφ-Leu-Val-Lys-Gly-Arg-Lys6-OH (GLP- 1 - (7-36)(Human)-Lys6-OH) on TentaGel S-PHB-Lys(Boc)Fmoc Dry TentaGel S-PHB-Lys(Boc)Fmoc resin (0.22 mmol/g, 500 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and swelled for two hours in DMF (5 ml). The Fmoc group on the first lysine was removed as described above and the synthesis was continued until finishing the peptide sequence as described under "Batchwise peptide synthesis on TentaGel S-PHB-Lys(Boc)Fmoc". After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method b as described above and freeze dried from acetic acid. The crude freeze dried product was purified twice by preparative HPLC using the procedure described above. The purified product was found to be homogeneous and the purity was found to be better than 98%. The identity of the peptide was confirmed by ES-MS. Yield 11 %. 30. Peptide synthesis of H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His- Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Tφ-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe- OH (PTH(l-34)(Human)-OH) on TentaGel S-NHg Dry TentaGel S-NH2 resin (0.31 mmol/g, 500 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and swelled for two hours in DMF (5 ml). The peptide according to the sequence was assembled as described under "Batchwise peptide synthesis on TentaGel S resins". After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method b as described above and freeze dried from acetic acid. The crude freeze dried peptide was purified twice by preparative HPLC using the procedure described above. The purified product was found to be homogeneous and the purity was found to be better than 98%. The identity of the peptide was confirmed by ES-MS. Yield 6.1 %. 31. Peptide synthesis of H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His- Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Tφ-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe- Lys6-OH (PTH(l-34)(Human)-Lys6-OH) on TentaGel S-PHB-Lys(Boc)Fmoc Dry TentaGel S-PHB-Lys(Boc)Fmoc resin (0.22 mmol/g, 500 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and swelled for two hours in DMF (5 ml). The Fmoc group on the first lysine was removed as described above. And the synthesis was continued until finishing the peptide sequence as described under "Batchwise peptide synthesis on TentaGel S-PHB-Lys(Boc)Fmoc". After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method b as described above and freeze dried from acetic acid. The crude freeze dried product was purified twice by preparative HPLC using the procedure described above. The purified product was found to be homogeneous and the purity was found to be better than 98%. The identity of the peptide was confirmed by ES-MS. Yield 5.3%. 32. Peptide synthesis of H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His- Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Tφ-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe- (Lys-Glu) 3 -OH (PTH 1-34 human-(Lys-Glu) 3 -OH) on NovaSyn TentaGel Dry NovaSyn TG resin (0.29 mmol/g, 250 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and treated as described under "batchwise peptide synthesis on PEG-PS" until finishing the peptide probe (Lys-Glu) 3 . The following amino acids forming the PTH sequence were coupled as preformed Fmoc-protected HObt esters (3 eq.) in DMF (5 ml) generated by means of DIC and the couplings were continued for at least 2 hours. The acylations were then checked by the ninhydrin test performed at 80°C as earlier described. After completion of the synthesis, the peptide-resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method c. The crude freeze dried product was analysed by HPLC and it was found to contain the target peptide together with impurities. The crude product was purified by preparative reverse-phase HPLC. The purity was found to be better than 98% and the identity of the peptide conjugate was confirmed by ES-MS. Yield 28%. 33. Peptide synthesis of H-(Lys)6-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly- Lys-His-Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Tφ-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His- Asn-Phe-OH (Lys6-PTH(l-34)(Human)-OH) on TentaGel S-NHg Dry TentaGel S-NH2 resin (0.31 mmol/g, 500 mg) was placed in a polyethylene vessel equipped with a polypropylene filter for filtration and swelled for two hours in DMF (5 ml). The peptide according to the sequence was assembled as described under "Batchwise peptide synthesis on TentaGel S resins". After completion of the synthesis, the peptide- resin was washed with DMF (3x5 ml, 1 min each), DCM (3x5 ml, 1 min each), diethyl ether (3x5 ml, 1 min each) and dried in vacuo. The peptide was cleaved from the resin according to method b as described above and freeze dried from acetic acid. The crude freeze dried product was purified twice by preparative HPLC using the procedure described above. The purified product was found to be homogeneous and the purity was found to be better than 90%. The identity of the peptide was confirmed by ES-MS. Yield 6.2 %. IN VITRO KINETIC MEASUREMENTS HPLC Gradient HPLC analysis of samples from in vitro kinetic measurements performed as described below was performed using a Hewlett Packard HP 1100 HPLC system consisting of a HP 1100 Binary Pump, a HP 1100 Autosampler, a HP 1100 Column Thermostat and a HP 1100 Variable Wavelength Detector. A Merck LiChroCART column (125 x 4 mm I.D.) and a LiChroCART precolumn (4 x 4 mm I.D.) packed with Lichrospher RP-18 (5 μm particles) was used. The column was kept at 25°C or 75°C and the column effluent was measured by UV detection at 215 nm. Separation of the peptide conjugates or the native peptides from degradation products and constituents of the reaction solutions was accomplished using gradient elution of the column with mixtures of mobile phase A (0.1 vol% TFA in water) and mobile phase B (0.085 vol% TFA in acetonitrile) at a flow rate of 1 ml/min. The following linear gradients used are shown in Table 1 below: Table 1 HYDROLYSIS KINETICS IN ENZYME SOLUTION The degradation of the peptide conjugate and the corresponding native peptide were studied at 37°C in a 50 mM phosphate buffer solution at pH 7.4 containing leucine aminopeptidase 5 (25 U/ml) or carboxypeptidase A (1 or 25 U/ml). Experiments were initiated by addition of an aliquot (100 μl) of a stock solution (1 mg/ml) of the peptide conjugate or the native peptide to 900 μl preheated enzyme solution giving a final concentration of ~ 0.1 mg/ml (10 "5 - 10 "4 M) of the peptide conjugate or the native peptide. The peptide/enzyme solution was kept at 37°C using a SHT200D block heater from Stuart Scientific. At appropriate time 10 intervals, samples of 100 μl were withdrawn from the peptide/enzyme solution, mixed thoroughly with 20 μl 25% TFA in acetonitrile in order to stop the enzymatic degradation process and analysed by HPLC as described above. Half-lives (tj /2 ) for the peptide conjugate and the coπesponding native peptide in the enzyme solutions were calculated from plots of the natural logarithm to the concentration of the residual peptide (HPLC peak 1 5 heights) against time using the formula t/ 2 =l/kobs x ln(2), where kobs is the apparent first- order rate constant for the observed degradation. H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu- Arg-Val-GIu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-OH (PTH(l- 20 34)(Human)-OH) Hydrolysis kinetics in leucine aminopeptidase The degradation of H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu- Asn-Ser-Met-Glu-Arg-Val-Glu-Tφ-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-OH 25 (~ 2.4 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 2.1 x 10 "3 min "1 and the corresponding half- life calculated to 330 min as previously described. Hydrolysis kinetics in carboxypeptidase A The degradation of H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu- Asn-Ser-Met-Glu-Arg-Val-Glu-Tφ-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-OH (~ 2.4 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing carboxypeptidase A (1 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 5.2 min "1 and the corresponding half-life calculated to 0.13 min as previously described. H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu- Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-(Lys) 6 -OH (PTH(l-34)(Human)-(Lys) 6 -OH) Hydrolysis kinetics in leucine aminopeptidase The degradation of H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu- Asn-Ser-Met-Glu-Arg-Val-Glu-Tφ-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe- (Lys) 6 -OH (~ 2.0 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 1.2 x 10 " min " and the coπesponding half-life calculated to 578 min as previously described. Hydrolysis kinetics in carboxypeptidase A The degradation of H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu- Asn-Ser-Met-Glu-Arg-Val-Glu-Tφ-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe- (Lys) 6 -OH (~ 2.0 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing carboxypeptidase A (1 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 1.5 x 10 " min " and the corresponding half- life calculated to 47 min as previously described. H-(Lys) 6 -Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser- Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-GIn-Asp-Val-His-Asn-Phe-OH ((Lys) 6 -PTH(l-34)(Human)-OH) Hydrolysis kinetics in leucine aminopeptidase The degradation of H-(Lys) -Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His- Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Tφ-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe- OH (~ 2.0 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 3.5 x 10 "3 min "1 and the coπesponding half- life calculated to 198 min as previously described. H-His-Ala-GIu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala- Ala-Lys-GIu-Phe-Ile-AIa-Trp-Leu-Val-Lys-Gly-Arg-OH (GLP-l(7-36)(Human)-OH) Hydrolysis kinetics in leucine aminopeptidase The degradation of H-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu- Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Tφ-Leu-Val-Lys-Gly-Arg-OH (~ 3.0 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 3.1 x 10 "2 min "1 and the coπesponding half-life calculated to 22 min as previously described. Hydrolysis kinetics in carboxypeptidase A The degradation of H-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu- Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Tφ-Leu-Val-Lys-Gly-Arg-OH (~ 3.0 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing carboxypeptidase A (1 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 4.7 x 10 "3 min "1 and the corresponding half-life calculated to 148 min as previously described. H-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala- AIa-Lys-GIu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-(Lys) 6 -OH (GLP-l(7- 36)(Human)-(Lys) 6 -OH) Hydrolysis kinetics in leucine aminopeptidase The degradation of H-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu- Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Tφ-Leu-Val-Lys-Gly-Arg-(Lys) 6 -OH (~ 2.5 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 1.3 x 10 " mm " and the coπesponding half-life calculated to 53 min as previously described. Hydrolysis kinetics in carboxypeptidase A The degradation of H-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu- Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Tφ-Leu-Val-Lys-Gly-Arg-(Lys) 6 -OH (~ 2.5 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing carboxypeptidase A (1 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 8 x 10 "3 min "1 and the coπesponding half-life calculated to 87 as previously described. H-Gly-Gly-Thr-Tyr-Ser-Cys-His-Phe-Gly-Pro-Leu-Thr-Trp-Val-Cys-Lys-Pro-Gln- Gly-Gly-OH (EMP-1 -OH) Hydrolysis kinetics in leucine aminopeptidase The degradation of H-Gly-Gly-Thr-Tyr-Ser-Cys-His-Phe-Gly-Pro-Leu-Thr-Tφ-Val-Cys- Lys-Pro-Gln-Gly-Gly-OH (~ 4.8 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 1.5 x 10 "3 min "1 and the coπesponding half-life calculated to 462 min as previously described. Hydrolysis kinetics in carboxypeptidase A The degradation of H-Gly-Gly-Thr-Tyr-Ser-Cys-His-Phe-Gly-Pro- Leu-Thr-Tφ-Val-Cys-Lys-Pro-Gln-Gly-Gly-OH (~ 4.8 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing carboxypeptidase A (1 U/ml) was studied as described above. A half-life of more than 50 hours was estimated for the degradation. H-Gly-Gly-Thr-Tyr-Ser-Cys-His-Phe-Gly-Pro-Leu-Thr-Trp-Val-Cys-Lys-Pro-Gln- Gly-Gly-(Lys) 6 -OH (EMP-l-(Lys) 6 -OH) Hydrolysis kinetics in leucine aminopeptidase The degradation of H-Gly-Gly-Thr-Tyr-Ser-Cys-His-Phe-Gly-Pro-Leu-Thr-Tφ-Val-Cys- Lys-Pro-Gln-Gly-Gly-(Lys) 6 -OH (~ 3.5 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. A half life of more than 100 hours was estimated for the degradation. Hydrolysis kinetics in carboxypeptidase A The degradation of H-Gly-Gly-Thr-Tyr-Ser-Cys-His-Phe-Gly-Pro- Leu-Thr-Tφ-Val-Cys-Lys-Pro-Gln-Gly-Gly-(Lys) 6 -OH (~ 3.5 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing carboxypeptidase A (1 U/ml) was studied as described above. A half-life of more than 20 hours was estimated for the degradation. H-(Lys) 6 -Gly-Gly-Thr-Tyr-Ser-Cys-His-Phe-Gly-Pro-Leu-Thr-Trp-Val-Cys-Lys-Pro- Gln-Gly-GIy-OH ((Lys) 6 -EMP-l-OH) Hydrolysis kinetics in leucine aminopeptidase The degradation of H-(Lys) 6 -Gly-Gly-Thr-Tyr-Ser-Cys-His-Phe-Gly-Pro-Leu-Thr-Tφ-Val- Cys-Lys-Pro-Gln-Gly-Gly-OH (~ 3.5 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. A half life of more than 24 hours was estimated for the degradation. H-(Lys) 6 -Gly-Gly-Thr-Tyr-Ser-Cys-His-Phe-Gly-Pro-Leu-Thr-Trp-Val-Cys-Lys-Pro- Gln-Gly-Gly-(Lys) 6 -OH ((Lys) 6 -EMP-l-(Lys) 6 -OH) Hydrolysis kinetics in leucine aminopeptidase The degradation of H-(Lys) 6 -Gly-Gly-Thr-Tyr-Ser-Cys-His-Phe-Gly-Pro-Leu-Thr-Tφ-Val- Cys-Lys-Pro-Gln-Gly-Gly-(Lys) 6 -OH (~ 2.8 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. A half life of more than 100 hours was estimated for the degradation. H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH 2 (substance P) Hydrolysis kinetics in leucine aminopeptidase The degradation of H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH 2 (~ 7.4 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 4.5 x 10 "2 min "1 and the coπesponding half-life calculated to 16 min as previously described. Hydrolysis kinetics in carboxypeptidase A The degradation of H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH 2 (~ 7.4 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing carboxypeptidase A (1 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was • 1 estimated to 2.0 x 10 " min " and the coπesponding half-life calculated to 35 min as previously described. H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-(Lys) 6 -NH 2 (Substance P-(Lys) 6 - NH 2 ) Hydrolysis kinetics in leucine aminopeptidase The degradation of H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-(Lys) 6 -NH 2 (~ 4.7 x 10 " M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 1.1 x 10 "2 min "1 and the corresponding half- life calculated to 66 min as previously described. Hydrolysis kinetics in carboxypeptidase A The degradation of H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-(Lys) 6 -NH 2 (~ 4.7 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing carboxypeptidase A (1 U/ml) was studied as described above. The pseudo first-order rate constant for the ddeeggrraaddaattiioonn wwaass eessttiimmaatteedd ttoo 55..f5 x 10 " min " and the coπesponding half-life calculated to 126 min as previously described. H-(Lys) 6 -Arg-Pro-Lys-Pro-Gln-GIn-Phe-Phe-Gly-Leu-Met-NH 2 ((Lys) 6 - Substance P-NH 2 ) Hydrolysis kinetics in leucine aminopeptidase The degradation of H-(Lys) 6 -Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH 2 (~ 4.7 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 2 x 10 " min " and the coπesponding half-life calculated to 347 min as previously described. H-Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu-OH (DSIP) Hydrolysis kinetics in leucine aminopeptidase The degradation of H-Tφ-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu-OH (~10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. The half-life was calculated to be less than 20 min. H-Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu-(Lys-Glu) 3 -OH (DSIP-(Lys-Glu) 3 -OH) Hydrolysis kinetics in leucine aminopeptidase The degradation of H-Tφ-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu-(Lys-Glu) 3 -OH (~10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was determined as described earlier and the half-life calculated to be 145 min. H-Tyr-Gly-Gly-Phe-Leu-OH (Leu-Enkephalin) Hydrolysis kinetics in leucine aminopeptidase The degradation H-Tyr-Gly-Gly-Phe-Leu-OH (~ 1.8 x 10 "4 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 6.8 x 10 " ' min "1 and the corresponding half-life calculated to 1.0 min as previously described. Hydrolysis kinetics in carboxypeptidase A The degradation H-Tyr-Gly-Gly-Phe-Leu-OH (~ 1.8 x 10 "4 M) in 50 mM phosphate buffer solutions of pH 7.4 containing carboxypeptidase A (1 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 9.8 x 10 "1 min "1 and the corresponding half-life calculated to 0.7 min as previously described. H-Tyr-Gly-Gly-Phe-Leu-(Lys) 6 -OH (Leu-Enkephalin-(Lys) 6 -OH) Hydrolysis kinetics in leucine aminopeptidase The degradation H-Tyr-Gly-Gly-Phe-Leu-(Lys) 6 -OH (~ 7.5 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 9.7 x 10 " min " and the coπesponding half-life calculated to 72 min as previously described. Hydrolysis kinetics in carboxypeptidase A The degradation H-Tyr-Gly-Gly-Phe-Leu-(Lys) 6 -OH (~ 7.5 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing carboxypeptidase A (1 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 7 x 10 "4 min "1 and the coπesponding half-life calculated to 990 min as previously described. H-(Lys) 6 -Tyr-Gly-Gly-Phe-Leu-OH ((Lys) 6 -Leu-Enkephalin-OH) Hydrolysis kinetics in leucine aminopeptidase The degradation H-(Lys) 6 -Tyr-Gly-Gly-Phe-Leu-OH (~ 7.5 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 2.6 x 10 "2 min "1 and the coπesponding half-life calculated to 27 min as previously described. H-(Lys) 6 -Tyr-Gly-Gly-Phe-Leu-(Lys) 6 -OH ((Lys) 6 -Leu-Enkephalin-(Lys) 6 -OH) Hydrolysis kinetics in leucine aminopeptidase The degradation H-(Lys) 6 -Tyr-Gly-Gly-Phe-Leu-(Lys) 6 -OH (~ 4.8 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. A half life of more than 100 hours was estimated for the degradation. H-Tyr-Gly-Gly-Phe-Leu-(Lys)ιo-OH (Leu-Enkephalin-(Lys)ιo-OH) Hydrolysis kinetics in leucine aminopeptidase The degradation H-Tyr-Gly-Gly-Phe-Leu-(Lys) 10 -OH (~ 5.4 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. A half-life of more than 100 hours was estimated for the degradation. Hydrolysis kinetics in carboxypeptidase A The degradation H-Tyr-Gly-Gly-Phe-Leu-(Lys)ι 0 -OH (~ 5.4 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing carboxypeptidase A (1 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 3 x 10 "4 min "1 and the coπesponding half-life calculated to 2310 min as previously described. H-Tyr-Gly-Gly-Phe-Leu-(Orn) 6 -OH (Leu-Enkephalin-(Orn) 6 -OH) Hydrolysis kinetics in leucine aminopeptidase The degradation H-Tyr-Gly-Gly-Phe-Leu-(Orn) 6 -OH (~ 5.7 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 6.4 x 10 "3 min "1 and the coπesponding half-life calculated to 108 min as previously described. Hydrolysis kinetics in carboxypeptidase A The degradation H-Tyr-Gly-Gly-Phe-Leu-(Orn) 6 -OH (~ 5.7 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing carboxypeptidase A (1 U/ml) was studied as described above. A half-life of more than 100 hours was estimated for the degradation. H-Tyr-Gly-Gly-Phe-Leu-(Dbu) 6 -OH (Leu-Enkephalin-(Dbu) 6 -OH) Hydrolysis kinetics in leucine aminopeptidase The degradation H-Tyr-Gly-Gly-Phe-Leu-(Dbu) 6 -OH (~ 6.0 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to i 2.5 x 10 " min " and the coπesponding half-life calculated to 28 min as previously described. Hydrolysis kinetics in carboxypeptidase A The degradation H-Tyr-Gly-Gly-Phe-Leu-(Dbu) 6 -OH (~ 6.0 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing carboxypeptidase A (1 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 5 x 10 " min "1 and the coπesponding half-life calculated to 1386 min as previously described. H-Tyr-Gly-Gly-Phe-Leu-(Dpr) 6 -OH (Leu-Enkephalin-(Dpr) 6 -OH) Hydrolysis kinetics in leucine aminopeptidase The degradation H-Tyr-Gly-Gly-Phe-Leu-(Dpr) 6 -OH (~ 6.3 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 1.7 x 10 "1 min "1 and the coπesponding half-life calculated to 4.2 min as previously described. Hydrolysis kinetics in carboxypeptidase A The degradation H-Tyr-Gly-Gly-Phe-Leu-(Dpr) 6 -OH (~ 6.3 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing carboxypeptidase A (1 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 2.4 x 10 "2 min "1 and the corresponding half-life calculated to 29 min as previously described. H-Tyr-GIy-Gly-Phe-Leu-Lys(Glu) 4 -Lys-OH (Leu-Enkephalin-Lys-(Glu) 4 -Lys-OH) Hydrolysis kinetics in leucine aminopeptidase The degradation H-Tyr-Gly-Gly-Phe-Leu-Lys-(Glu) 4 -Lys-OH (~ 7.5 x 10 '5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 6.5 x 10 "2 min "1 and the coπesponding half-life calculated to 11 min as previously described. Hydrolysis kinetics in carboxypeptidase A The degradation H-Tyr-Gly-Gly-Phe-Leu-Lys-(Glu) 4 -Lys-OH (~ 7.5 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing carboxypeptidase A (1 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 6 x 10 "4 min "1 and the coπesponding half-life calculated to 1155 min as previously described. H-Tyr-Gly-Gly-Phe-Leu-Lys-(GIu) 3 -(Lys) 2 -OH (Leu-Enkephalin-Lys-(Glu) 3 -(Lys) 2 - OH) Hydrolysis kinetics in leucine aminopeptidase The degradation H-Tyr-Gly-Gly-Phe-Leu-Lys-(Glu) 3 -(Lys) 2 -OH (~ 7.5 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing leucine aminopeptidase (25 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 1.2 x 10 "1 min "1 and the coπesponding half-life calculated to 5.7 min as previously described. Hydrolysis kinetics in carboxypeptidase A The degradation H-Tyr-Gly-Gly-Phe-Leu-Lys-(Glu) 3 -(Lys) 2 -OH (~ 7.5 x 10 "5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing carboxypeptidase A (1 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 8 x 10 "4 min "1 and the corresponding half-life calculated to 866 min as previously described. Studies with Enkephalin Analogues Bioavailability of Leu-enkephalin-OH and Leu-enkephalin-(Lys) 6 -OH in mice Male mice weighing 20-25 g were given 50 mg Leu-enkephalin-(Lys) -OH per kg body weight i.v. or p.o. The compound was dissolved in isotonic NaCl solution. Mice treated with Leu-enkephalin-(Lys) 6 -OH, 50 mg/kg p.o. were bled by decapitation at 0, 15, 30, 60, 90, 240, 480, 960 and 1380 minutes after dosing. Mice treated with Leu-enkephalin-(Lys) 6 - OH, 50 mg/kg i.v. were bled by decapitation at 5, 15, 30, 60, 180, 240, 370, 720, 1080, and 1440 minutes after dosing. Animals treated with the native Leu-enkephalin-OH, 50 mg/kg p.o. or i.v. were bled by decapitation 30 min after dosing. Blood samples were centrifuged immediately (3000 g, 4°C) and serum was isolated and used for activity determination. The concentrations of Leu-enkephalin-OH or Leu-enkephalin-(Lys) -OH in serum were determined by a bioassay using the vas deferens model from mice. Experiments were carried out essentially as described by Takemori and Porthogese, 1984, Ewr. J. Pharmacol. 104:101-104. In short: vasa deferentia were isolated from male mice weighing 20-30 g (Møllegaard breeding, DK) and suspended through two electrodes in 10 ml baths at resting tension of 1 g. The tissues were bathed with Krebs-bicarbonate solution (physiological buffer solution) maintained at 36-37°C and continously bubbled with 95 % O 2 and 5 % CO 2 . The tissues were stimulated electrically (70 V, 1 ms duration; 0.1 Hz) and contractions were recorded isometrically on a chart recorder. After equilibration of the tissue for at least 20 min, drugs were added in the bath and the maximum effects were measured. Data were fitted to the equation % Inhibition = MAX x (1- [Inh] ([Inh] n + IC 50 n )) + baseline, where MAX is the maximum muscle contraction, [Inh] is the concentration of the inhibitor, n is the Hill slope of the curve and baseline is the muscle contraction insensitive to the compound. Thus, the calculated concentration is a reflection of inhibitory activity in the vas deferens bioassay preparation and not an exact measure of Leu-enkephalin-OH or Leu- enkephalin-(Lys) 6 -OH in serum. Values for Leu-enkephalin-OH and Leu-enkephalin-(Lys)6-oH are mean values ± S.Ε.M of at least 5 experiments. In assays where the concentration of Leu-enkephalin-(Lys)6-oH in serum was determined, 100 μl of serum was added to the tissue bath and the % inhibition of the response was determined. The results are shown in Table 2. Table 2: Functional activity in serum after p.o. or i.v. administration of Leu-enkephalin-(Lys) 6 -OH in mice (n=6-8 serum samples per time point; mean ±S.E.M.). N/A: Non Applicable Following an i.v. injection of 50 mg per kg body weight of Leu-enkephalin-(Lys) -OH, a rapid increase in activity was observed in serum already after 5 min. Then, activity declined within the following 30 min, but between 240 min (4 hrs) and 720 min (12 hrs), the activity reached a second peak level. The second peak was possibly related to enterohepatic circulation of the drug after i.v. administration. Activity in plasma was below the detection limit at 12, 18 and 24 hours after i.v. administration of Leu-enkephalin-(Lys) 6 -OH. After p.o. administration of Leu-enkephalin-(Lys) 6 -OH, the activity in serum reached a maximum at 90-240 min (1.5-4 hrs) and activity was detectable after 8, and 16 hrs, but not after 23 hrs. While high activities were observed at 30 min in serum samples from animals treated with Leu-enkephalin-(Lys) 6 -OH either p.o. or i.v., no activity was detected 30 min after p.o. or i.v. administration of the native Leu-enkephalin-OH. These results suggest that Leu-enkephalin-(Lys) -OH, but not Leu-enkephalin-OH, is absorbed after p.o. administration and that the elimination rate in serum is substantially reduced relative to the native Leu-enkephalin in mice. Stability of Leu-enkephalin-OH and Leu-Enkephalin-(Lys)(,-OH in mouse plasma at 37°C The stability of Leu-enkephalin-OH, Leu-Enkephalin-(Lys) 6 -OH, Leu-Enkephalin-(Glu 2 - Lys-Glu )-OH, Leu-Enkephalin-(Lys-Glu -Lys)-OH, Leu-Enkephalin-(ORN) -OH, Leu- Enkephalin-(DBU) 6 -OH, Leu-Enkephalin-(DPR) 6 -OH, and Leu-Enkephalin-(Lys)ιo-OH in mouse plasma at 37°C was examined in the vas deferens bioassay model as described above. Prior to addition of the plasma sample, a standard dose-response curve was generated in each preparation in order to express the inhibitory activity as concentration of each test substance. Thus, the calculated concentration is a reflection of inhibitory activity in the vas deferens bioassay preparation. Dose-response data were fitted to the equation: Response = Initial value • (1 - (conc/EC50+conc)) + background Where initial = initial helically-induced contraction force prior to addition of test substance; cone = concentration of test substance; EC50 = concentration of test substance that produced half maximal inhibition of electrically-induced contraction; background = contraction force during maximal relaxation. All enkephalin analogues were dissolved in Krebs buffer in a concentration of 1 mM. Sixty- six μl of each test substance solution (66 nmol enkephalin analog) was incubated with 600 μl plasma at 37°C. At different time points (2-120 min), 10 μl samples were withdrawn for analysis of functional activity. Functional activity of each test substance in plasma was expressed as the concentration of the test substance that elicited the same inhibition of electrically-induced contraction in the vas deferens bioassay. Tl/2 was calculated by fitting the time-concentration data to the equation: cone (t) = conc(0) • e ( - ,n2m/2)'t where conc(0) = concentration at t=0. The results are shown in Table 3. ND: Not determined. These data suggest that modifications of Leu-Enkephalin-OH increased the EC50 value and increased the stablity in mouse plasma at 37°C. μ-Receptor binding of Leu-enkephalin-OH analogues Affinities for μ opioid receptor were determined using [ 3 H](D-Ala 2 ,N-Me-Phe 4 , Gly-ol 5 ) Enkephalin (DAMGO) (1 nM) as described by Christensen, 1993, Pharmacol. Toxicol. 73:344-345. In short: Bovine brains were placed on ice within minutes after the slaughter. The caudate nuclei were dissected and homogenized in 20 vol. of 0.32 M sucrose. The homogenate was centrifuged at 2000 g for 10 min. The pellet was re-suspended in 10 vol. of 50 mM Tris-HCl buffer 7.4 and stored at -20 °C until use. The synaptic membrane fraction was incubated with 1 nM of [3H]DAMGO in the presence of various concentrations of test ligand. Non specifically bound [3HJ-DAMGO was established using 1 μM naloxone. Following 15 min. incubation at 36 °C samples were filtered through Whatman GF/C filters and washed with buffer. Radioactivity was determined using conventional techniques. As shown in Table 4 below, all compounds were active in this binding assay, indicating that modification of Leu-enkephalin-OH affects receptor affinity. Table 4: Affinity of Leu-Enkephalin-OH analogues at μ opioid receptors measured as 3 H-DAMGO binding (IC 50 values (mean ± SD). The low affinity of Leu-Enkephalin-(Glu) 6 -OH relative to the other test substances may be due to the very low solubility of this compound. Thus, the IC 50 value of Leu-Enkephalin- (Glu) 6 -OH may be lower if tested in a solvent in which the compound is more soluble. In vivo experiments with EMP-l-K^ in mice To examine the biological efficacy of peroral (p.o.) treatment with EMP-1 and EMP-1 -K 6 , the hematological responses of an equimolar p.o. dose (956 nmol) of EMP-1 (2 mg) and EMP-1-K (2.56 mg) were examined in male mice (n=8/group). To examine the time course of the hematological responses, a 10 μl venous blood sample was collected from the retroorbital plexus on days 0, 2, and 4. Body weight (BW) and the plasma concentration of hemoglobin (P-Hgb), the hematocrit value (Hct), the red blood cell count (RBC), and the mean cell hemoglobin concentration (MCHC) were determined before (Day 0), and 2 and 4 days after administration of EMP-1 or EMP-1- K 6 . The results are shown in Table 5. Table 5: Changes in body weight and in hematological parameters 4 days after p.o. administration of 956 nmol EMP-1 or EMP-1 -Y^. Relative changes are presented in parenthesis (mean ± SEM). *: p<0.05 vs. EMP-1 p.o. These data show that the p.o. administration of 2.56 mg EMP-1-K produces a significantly greater increase in P-hgb, Hct, and RBC than the equimolar dose of EMP-1 p.o. None of the compounds affected growth or MCHC. These results suggests that EMP-1 -K is absorbed after p.o. administration and that it elicits a rapid stimulation of the erythropoiesis in mice. STUDIES WITH PARATHYROID HORMONE (PTH) ANALOGUES General Procedures Osteoblast retraction assay Retraction assays were performed with osteoblast prepared from calvaria of 1-day old mice according to published protocols (Miller et al., 1976, Science 192:1340-1343). In brief, osteoblasts were seeded in serum-free minimal essential medium-α (αMEM) at a density of 3000 cells per cm 2 into 96- well tissue culture plates coated with 50 μg/ml of type I collagen in phosphate-buffered saline containing 0.1% bovine serum albumin (PBS). One day after plating, PTH compounds were added to a final concentration of 10 nM and incubation was carried out for 1 h. Cells were then fixed and stained with toluidine blue, and the number of retracted cells was counted by visual inspection. PTH itself is able retract some 64% of the cells compared to blanks where only 10-12 % of the cells are retracted. Enzyme immunoassay (EIA) for human PTH ( 1 -34) This is a standard EIA assay (EIAS(h)-6101 from Peninsula Laboratories, Inc.) Biotinylated peptide and peptide competes for binding to PTH (l-34)-antibody. Streptavidin-conjugated Horseradish Peroxidase (SA-HRP) is allowed to bind to the primary antibody/biotinylated peptide complex. 3,3',5,5'-Tetramethyl Benzidine Dihydrochloride (TMB) is allowed to react with the bound HRP. The colour intensity is used to quantification. Specificity of the assay: hPTH(l-34) = 100%; hPTH(l-38) = 100%; hPTH(l-44) = 0%; hPTH(39-68) = 0%; hPTH(l-84) - 0%; ratPTH(l-34) = 0%. The results are shown in Table 6. In the Osteoblast retraction assay, hPTH(l-34) retains approximately 89% of the activity of native, human parathyroid hormone. H-hPTH(l-34)- K 6 -OH and H-K 6 -PTH(l-34)-OH show 55 and 49%, respectively of the activity of the mother compound hPTH(l-34). The antibody towards hPTH(l-34) used in EIA recognises the two modifications well. Table 6 Functional activity of Substance P-NH 2 and (Lys) 6 -Substance P-NH . The functional activity of Substance P-NH 2 and (Lys) -Substance P-NH 2 were characterized using the guinea pig illeum. Experiments were carried out essentially as described by Kristiansen et al., 1992, Br. J. Pharmacol. 58:1 150) with the modification that the illeum was not electrically stimulated. Following application of the compounds the induced contraction was measured. Dose-response data were fitted to the equation: Response = Initial value • conc/(EC50+conc) Where initial value = initial electrically-induced contraction force prior to addition of test substance; cone = concentration of test substance; EC50 = concentration of test substance that produced half maximal inhibition of electrically-induced contraction SubstanceP-NH 2 (EC50 = 40 nM) and (Lys) 6 -SubstanceP-NH 2 (EC50= 5 nM) both acted as agonists at the guinea pig illeum. The invention described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed, since these embodiments are intended as illustrations of several aspects of the invention. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Various references are cited herein, the disclosure of which are incoφorated by reference in their entireties.

Claims: WHAT IS CLAIMED IS: 1. A pharmacologically active peptide conjugate having a reduced tendency towards enzymatic cleavage comprising X and Z, wherein X is a pharmacologically active peptide sequence, and wherein Z is a stabilising peptide sequence, of 4-20 amino acid units covalently bound to X, wherein each amino acid unit in said stabilising peptide sequence, Z is selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His, Met, Orn, and amino acid units of the general formula I -NH-C(R")(R 2 )-C(=O)- (I) wherein R 1 and R 2 are selected from the group consisting of hydrogen, Cι -6 -alkyl, phenyl, and phenyl-methyl, wherein Cj -6 -alkyl is optionally substituted with from one to three substituents selected from halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, and phenyl and phenyl-methyl is optionally substituted with from one to three substituents selected from Cι- -alkyl, C 2-6 -alkenyl, halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, or R 1 and R 2 together with the carbon atom to which they are bound form a cyclopentyl, cyclohexyl, or cycloheptyl ring, e.g. 2,4-diaminobutanoic acid and 2,3- diaminopropanoic acid; and wherein the ratio between the half-life of said peptide conjugate and the half-life of the coπesponding pharmacologically active peptide sequence, X, when treated with carboxypeptidase A or leucine aminopeptidase in about 50 mM phosphate buffer solution at about pH 7.4 at about 37°C or in serum or plasma is at least about 2, preferably at least about 3, such as at least about 5, more preferably at least about 7, such as at least about 9, e.g. at least about 10 or when said pharmacologically active peptide X is not orally absorbed, said conjugate is absorbed, or a salt thereof, with the proviso that said pharmacologically active peptide conjugate is not selected from H-Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu-(Lys-Glu) 3 -OH, H-Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu-(Glu) 6 -OH, H-Tyr-Gly-Gly-Phe-Leu-(Glu) 6 -OH and H-Tyr-Gly-Gly-Phe-Leu-(Lys) 6 -OH. 2. A peptide conjugate according to claim 1, wherein Z is covalently bound to X at the C- terminal carbonyl function of X. 3. A peptide conjugate according to claim 1, wherein Z is covalently bound to the N- terminal nitrogen atom of X. 4. A peptide conjugate according to claim 1, wherein the first sequence (Z) is covalently bound to X at the C-terminal carbonyl function of X and the second sequence (Z) is covalently bound to the N-terminal nitrogen atom of X. 5. A peptide conjugate according to claim 1, wherein Z is covalently bound to a nitrogen atom on the side chain of a lysine, arginine or histidine residue or a carbonyl function on the side chain of glutamic acid or aspartic acid of X. 6. A peptide conjugate according to any of the preceding claims, wherein Z consists of 4- 15, preferably 4-10, more preferably 4-7, such as 6 amino acid units. 7. A peptide conjugate according to claim 5 or 6, wherein each amino acid unit in Z is independently selected from the group consisting of Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His, Orn, 2,4-diaminobutanoic acid, 2,3-diaminopropanoic acid and Met. 8. A peptide conjugate according to claim 7, wherein each amino acid unit in Z is selected from the group consisting of Glu, Lys and Met. 9. A peptide conjugate according to any of claims 5 to 8, wherein Z comprises at least one Lys amino acid unit, preferably at least two Lys amino acid units, such as at least three Lys amino acid units, e.g. at least four Lys amino acid units, more preferably at least five Lys amino acid units, such as six Lys amino acid units. 10. A peptide conjugate according to claim 9, wherein Z is (Lys) n , wherein n is an integer in the range from 4 to 15, preferably in the range from 4 to 10, such as in the range from 4 to 8, e.g. in the range from 4 to 6. 11. A peptide conjugate according to claim 9, wherein Z is Lys , Lys 5 or Lys 6 . 12. A peptide conjugate according to claim 11 , wherein Z is Lys 6 . 13. A peptide conjugate according to any of claims 5 to 9, wherein Z is (Lys-Xaa) m or (Xaa-Lys) m , wherein m is an integer in the range from 2 to 7, and each Xaa is independently selected from the group consisting of Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Arg, His, Orn, 2,4- diaminobutanoic acid, 2,3-diaminopropanoic acid and Met. 14. A peptide conjugate according to claim 13, wherein Z is (Lys-Xaa) 3 or (Xaa-Lys) 3 , wherein each Xaa is independently selected from the group consisting of Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Arg, His, Orn, 2,4-diaminobutanoic acid, 2,3-diaminopropanoic acid and Met. 15. A peptide conjugate according to claim 15, wherein Z is (Lys-Glu) 3 or (Glu-Lys) 3 . 16. A peptide conjugate according to any of claims 5 to 9, wherein Z is Lys p -Xaaq or Xaa p -Lys q , wherein p and q are integers in the range from 1 to 14, with the proviso that p+q is in the range of 3-15, and each Xaa is independently selected from the group consisting of Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Arg, His, Orn, 2,4-diaminobutanoic acid, 2,3- diaminopropanoic acid and Met. 17. A peptide conjugate according to claim 16, wherein Z is Lys 3 -Xaa 3 or Xaa 3 -Lys 3 , wherein each Xaa is independently selected from the group consisting of Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Arg, His, Orn, 2,4-diaminobutanoic acid, 2,3-diaminopropanoic acid and Met. 18. A peptide conjugate according to claim 17, wherein Z is Lys 3 -Glu 3 or Glu 3 -Lys , 19. A peptide conjugate according to claims 5-18, wherein Z is Lys-Lys-Lys-Lys, Xaa-Lys- Lys-Lys, Lys-Xaa-Lys-Lys, Lys-Lys-Xaa-Lys, Lys-Lys-Lys-Xaa, Xaa-Xaa-Lys-Lys, Xaa- Lys-Xaa-Lys, Xaa-Lys-Lys-Xaa, Lys-Xaa-Xaa-Lys, Lys-Xaa-Lys-Xaa, Lys-Lys-Xaa-Xaa, Xaa-Xaa-Xaa-Lys, Xaa-Xaa-Lys-Xaa, Xaa-Lys-Xaa-Xaa, Lys-Xaa-Xaa-Xaa, Xaa-Xaa- Xaa-Xaa, Lys-Lys-Lys-Lys-Lys, Xaa-Lys-Lys-Lys-Lys, Lys-Xaa-Lys-Lys-Lys, Lys-Lys- Xaa-Lys-Lys, Lys-Lys-Lys-Xaa-Lys, Lys-Lys-Lys-Lys-Xaa, Xaa-Xaa-Lys-Lys-Lys, Xaa- Lys-Xaa-Lys-Lys, Xaa-Lys-Lys-Xaa-Lys, Xaa-Lys-Lys-Lys-Xaa, Lys-Xaa-Xaa-Lys-Lys, Lys-Xaa-Lys-Xaa-Lys, Lys-Xaa-Lys-Lys-Xaa, Lys-Lys-Xaa-Xaa-Lys, Lys-Lys-Xaa-Lys- Xaa, Lys-Lys-Lys-Xaa-Xaa, Lys-Lys-Xaa-Xaa-Xaa, Lys-Xaa-Lys-Xaa-Xaa, Lys-Xaa-Xaa- Lys-Xaa, Lys-Xaa-Xaa-Xaa-Lys, Xaa-Lys-Lys-Xaa-Xaa, Xaa-Lys-Xaa-Xaa-Lys, Xaa-Xaa- Lys-Lys-Xaa, Xaa-Xaa-Lys-Xaa-Lys, Xaa-Xaa-Xaa-Lys-Lys, Lys-Xaa-Xaa-Xaa-Xaa, Xaa- Lys-Xaa-Xaa-Xaa, Xaa-Xaa-Lys-Xaa-Xaa, Xaa-Xaa-Xaa-Lys-Xaa, Xaa-Xaa-Xaa-Xaa-Lys, Xaa-Xaa-Xaa-Xaa-Xaa, Lys-Lys-Lys-Lys-Lys-Lys, Xaa-Lys-Lys-Lys-Lys-Lys, Lys-Xaa- Lys-Lys-Lys-Lys, Lys-Lys-Xaa-Lys-Lys-Lys, Lys-Lys-Lys-Xaa-Lys-Lys, Lys-Lys-Lys- Lys-Xaa-Lys, Lys-Lys-Lys-Lys-Lys-Xaa, Xaa-Xaa-Lys-Lys-Lys-Lys, Xaa-Lys-Xaa-Lys- Lys-Lys, Xaa-Lys-Lys-Xaa-Lys-Lys, Xaa-Lys-Lys-Lys-Xaa-Lys, Xaa-Lys-Lys-Lys-Lys- Xaa, Lys-Xaa-Xaa-Lys-Lys-Lys, Lys-Xaa-Lys-Xaa-Lys-Lys, Lys-Xaa-Lys-Lys-Xaa-Lys, Lys-Xaa-Lys-Lys-Lys-Xaa, Lys-Lys-Xaa-Xaa-Lys-Lys, Lys-Lys-Xaa-Lys-Xaa-Lys, Lys- Lys-Xaa-Lys-Lys-Xaa, Lys-Lys-Lys-Xaa-Xaa-Lys, Lys-Lys-Lys-Xaa-Lys-Xaa, Lys-Lys- Lys-Lys-Xaa-Xaa, Xaa-Xaa-Xaa-Lys-Lys-Lys, Xaa-Xaa-Lys-Xaa-Lys-Lys, Xaa-Xaa-Lys- Lys-Xaa-Lys, Xaa-Xaa-Lys-Lys-Lys-Xaa, Xaa-Lys-Xaa-Xaa-Lys-Lys, Xaa-Lys-Xaa-Lys- Xaa-Lys, Xaa-Lys-Xaa-Lys-Lys-Xaa, Xaa-Lys-Lys-Xaa-Xaa-Lys, Xaa-Lys-Lys-Xaa-Lys- Xaa, Xaa-Lys-Lys-Lys-Xaa-Xaa, Lys-Lys-Lys-Xaa-Xaa-Xaa, Lys-Lys-Xaa-Lys-Xaa-Xaa, Lys-Lys-Xaa-Xaa-Lys-Xaa, Lys-Lys-Xaa-Xaa-Xaa-Lys, Lys-Xaa-Lys-Lys-Xaa-Xaa, Lys- Xaa-Lys-Xaa-Lys-Xaa, Lys-Xaa-Lys-Xaa-Xaa-Lys, Lys-Xaa-Xaa-Lys-Lys-Xaa, Lys-Xaa- Xaa-Lys-Xaa-Lys, Lys-Xaa-Xaa-Xaa-Lys-Lys, Lys-Lys-Xaa-Xaa-Xaa-Xaa, Lys-Xaa-Lys- Xaa-Xaa-Xaa, Lys-Xaa-Xaa-Lys-Xaa-Xaa, Lys-Xaa-Xaa-Xaa-Lys-Xaa, Lys-Xaa-Xaa-Xaa- Xaa-Lys, Xaa-Lys-Lys-Xaa-Xaa-Xaa, Xaa-Lys-Xaa-Lys-Xaa-Xaa, Xaa-Lys-Xaa-Xaa-Lys- Xaa, Xaa-Lys-Xaa-Xaa-Xaa-Lys, Xaa-Xaa-Lys-Lys-Xaa-Xaa, Xaa-Xaa-Lys-Xaa-Lys-Xaa, 5 Xaa-Xaa-Lys-Xaa-Xaa-Lys, Xaa-Xaa-Xaa-Lys-Lys-Xaa, Xaa-Xaa-Xaa-Lys-Lys-Lys, Xaa- Xaa-Xaa-Lys-Xaa-Lys, Xaa-Xaa-Xaa-Xaa-Lys-Lys, Lys-Xaa-Xaa-Xaa-Xaa-Xaa, Xaa-Lys- Xaa-Xaa-Xaa-Xaa, Xaa-Xaa-Lys-Xaa-Xaa-Xaa, Xaa-Xaa-Xaa-Lys-Xaa-Xaa, Xaa-Xaa- Xaa-Xaa-Lys-Xaa, Xaa-Xaa-Xaa-Xaa-Xaa-Lys, or Xaa-Xaa-Xaa-Xaa-Xaa-Xaa, wherein each Xaa is independently selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, 10 Asn, Gin, Asp, Glu, Arg, His, Met, Orn, and amino acids of the formula I -NH-C(R')(R 2 )-C(=O)- (I) wherein R 1 and R 2 are selected from the group consisting of hydrogen, Cι -6 -alkyl, phenyl, 1 5 and phenyl-methyl, wherein Cι -6 -alkyl is optionally substituted with from one to three substituents selected from halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, and phenyl and phenyl-methyl is optionally substituted with from one to three substituents selected from Cι- -alkyl, C 2- -alkenyl, halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, or R 1 and R 2 together with the carbon atom to which they are bound form a 20 cyclopentyl, cyclohexyl, or cycloheptyl ring, e.g. 2,4-diaminobutanoic acid (Dbu) and 2,3- diaminopropanoic acid (Dpr). 20. A peptide conjugate according to any of claims 5 to 18, wherein Z consists of L-amino acids only. 25 21. A peptide conjugate according to any of claims 5-7, wherein Z is (Dbu) n or (Dpr) n , wherein n is an integer in the range from 4 to 15, preferably in the range from 4 to 10, such as in the range from 4 to 8, e.g. in the range from 4 to 6. 30 22. A peptide conjugate according to claim 1 , wherein Z is Dpr 6 . 23. A peptide conjugate according to any of the preceding claims, wherein said pharmacologically active peptide sequence (X) consists of at the most 75 amino acid units, such as at the most 65, e.g. a the most 60, preferably at the most 55, such as at the most 53, e.g. at the most 50. 24. The peptide conjugate according to claim 16, wherein X is selected from the group consisting of enkephalin, Leu-enkephalin, Met-enkephalin, angiotensin I, angiotensin II, vasopressin, endothelin, vasoactive intestinal peptide, neurotensin, endorphins, insulin, gramicidin, paracelsin, delta-sleep inducing peptide, gonadotropin-Releasing hormone, human parathyroid hormone (1-34), truncated erythropoietin analogues, specifically EMP-1, Atrial natriuretic peptide (ANP, ANF), human brain natriuretic peptide (hBNP), cecropin, kinetensin, neurophysins, elafin, guamerin, atriopeptin I, atriopeptin II, atriopeptin III, deltorphin I, deltorphin II, vasotocin, bradykinin, dynorphin, dynorphin A, dynorphin B, growth hormone release factor, growth hormone, growth hormone releasing peptide, oxytocin, calcitonin, calcitonin gene-related peptide, calcitonin gene-related peptide II, growth hormone releasing peptide, tachykinin, adrenocorticotropic hormone (ACTH), brain natriuretic polypeptide, cholecystokinin, corticotropin releasing factor, diazepam binding inhibitor fragment, FMRF-amide, galanin, gastric releasing polypeptide, gastric inhibitory polypeptide, gastrin, gastrin releasing peptide, glucagon, glucagon-like peptide- 1, glucagon- like peptide-2, LHRH, melanin concentrating hormone, melanocyte stimulating hormone (MSH), alpha-MSH, morphine modulating peptides, motilin, neurokinin A, neurokinin B, neuromedin B, neuromedin C, neuromedin K, neuromedin N, neuromedin U, neuropeptide K, neuropeptide Y, pituitary adenylate cyclase activating polypeptide (PACAP), pancreatic polypeptide, peptide YY, peptide histidine-methionine amide (PHM), secretin, somatostatin, substance K, thyrotropin-releasing hormone (TRH), kyotorphin, melanostatin (MIF-1), thrombopoeitin analogs, in particular AF 12505 (Ile-Glu-Gly-Pro-Thr-Leu-Arg- Gln-Trp-Leu-Ala-Ala-Arg-Ala), insulin-like growth factor I (57-70) (Ala-Leu-Leu-Glu- Thr-Tyr-Cys-Ala-Thr-Pro-Ala-Lys-Ser-Glu), insulin-like growth factor I (30-41) (Gly-Tyr- Gly-Ser-Ser-Ser-Arg-Arg-Ala-Pro-Gln-Thr), insulin-like growth factor I (24-41)(Tyr-Phe- Asn-Lys-Pro-Thr-Gly-Tyr-Gly-Ser-Ser-Ser-Arg-Arg-Ala-Pro-Gln-Thr) , insulin-like growth factor II (33-40) (Ser-Arg-Val-Ser-Arg-Arg-Ser-Arg), insulin-like growth [tyro] factor II (33-40) (Tyr-Ser-Arg-Val-Ser-Arg-Arg-Ser-Arg), insulin-like growth factor II (69-84) (Asp-Val-Ser-Thr-Pro-Pro-Thr-Val-Leu-Pro-Asp-Asn-Phe-Pro- Arg-Tyr), growth hormone (GH)-releasing peptide-6 (GHRP-6) (His-DTrp-Ala-Tφ-DPhe-Lys-NH2), beta-Interleukin I (163-171) (Val-Gln-Gly-Glu-Glu-Ser-Asn-Asp-Lys), beta-Interleukin II (44-56) (Ile-Leu- Asn-Gly-Ile-Asn-Asn-Tyr-Lys-Asn-Pro-Lys-Leu), Interleukin II (60-70) (Leu-Thr-Phe-Lys- Phe-Tyr-Met-Pro-Lys-Lys-Ala), exendin-4 (GLP-1 analog) (His-Gly-Glu-Gly-Thr-Phe-Thr- Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ue-Glu-Tφ-Leu-Lys- Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2), exendin-3 (GLP-1 analog) (His- Ser-Asp-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu- Phe-Ile-Glu-Tφ-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser), [Cys(Acm)20,31] epidermal growth factor (20-31) Cys(Acm)-Met-His-Ile-Glu-Ser-Leu- Asp-Ser-Tyr-Thr-Cys(Acm), bivalirudin (Hirulog) (D-Phe-Pro-Arg-Pro-(Gly)4-Asn-Gly- Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu), hirulog- 1 D-Phe-Pro-Arg-Pro-(Gly)4- Asn- Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Tyr-Leu, C-type natriuretic peptide (1-53) (CNP) (Asp- Leu-Arg-Val-Asp-Thr-Lys-Ser-Arg-Ala-Ala-Tφ-Ala-Arg-Leu-Leu-Gln-Glu-His-Pro-Asn- Ala-Arg-Lys-Tyr-Lys-Gly-Ala-Asn-Lys-Lys-Gly-Leu-Ser-Lys-Gly-Cys-Phe-Gly-Leu-Lys- Leu-Asp-Arg-Ile-Gly-Ser-Met-Ser-Gly-Leu-Gly-Cys; Disulfide bridge: Cys37-Cys53), "Mini ANP" (Met-Cys-His-cyclohexylAla-Gly-Gly-Arg-Met-Asp-Arg-Ile-Ser-Cys-Tyr- Arg s disulfide bridge cys2-cysl3), Melanotan-II (also known as MT-II, alpha-MSH4-10- NH2, or Ac-Nle4-Asp5-His6-D-Phe7-Arg8-Tφ9-Lysl0), thymosin alphal (TA1) (Ac-Ser- Asp-Ala-Ala- Val-Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu- Val-Val-Glu-Glu-Ala-Glu-Asn), ornipressin (also known as 8-ornithine-vasopressin, (POR-8), [Phe2,Ile3,Orn8]vasopressin), Cys-Phe-Ile-Gln-Asn-Cys-Pro-Orn-Gly-NH2, Disulfide bridge: Cysl-Cys6), octreotide (201-995) (DPhe-Cys-Phe-DTφ-Lys-Thr-Cys- Thr-ol; disulfide bridge: Cys2-Cys7), eptifibatide (INTEGRILIN), calcitonin gene-related peptide (CGRP) (Ala-Cys-Asp-Thr-Ala-Thr-Cys-Val-Thr-His-Arg-Leu-Ala-Gly-Leu-Leu- Ser-Arg-Ser-Gly-Gly-Val-Val-Lys-Asn-Asn-Phe-Val-Pro-Thr-Asn-Val-Gly-Ser-Lys-Ala- Phe-NH 2; Disulfide bridge: Cys2-Cys7), endomoφhin-1 Tyr-Pro-Tφ-Phe-NH2; endomoφhin-2 Tyr-Pro-Phe-Phe-NH 2 , nociceptin (also known as Oφhanin FQ, Phe-Gly- Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln), angiotensinogen (1 - 13) (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His), adrenomodullin (1-12) (Tyr- Arg-Gln-Ser-Met-Asn-Asn-Phe-Gln-Gly-Leu-Arg), antiarrhytmic peptide (AAP) (Gly-Pro- Hyp-Gly-Ala-Gly), Antagonist G (Arg-DTφ-(nMe)Phe-DTφ-Leu-Met-NH 2 ), indolicidin (Ile-Leu-Pro-Tφ-Lys-Tφ-Pro-Tφ-Tφ-Pro-Tφ-Arg-Arg-NH 2 ), osteocalcin (37-49) (Gly- Phe-Gln-Glu-Ala-Tyr-Arg-Arg-Phe-Tyr-Gly-Pro-Val), cortistatin 29 (1-13) (Glp)-Glu-Arg- Pro-Pro-Leu-Gln-Gln-Pro-Pro-His-Arg-Asp), cortistatin 14 Pro-Cys-Lys-Asn-Phe-Phe- Tφ-Lys-Thr-Phe-Ser-Ser-Cys-Lys; Disulfide bridge: Cys2-Cysl3, PD-145065 (Ac-D-Bhg- Leu-Asp-Ile-Ile-Tφ), PD- 142893 (Ac-D-Dip-Leu-Asp-Ile-Ile-Tφ), fibrinogen binding inhibitor peptide (His-His-Leu-Gly-Gly-Ala-Lys-Gln-Ala-Gly-Asp-Val), leptin (93-105) (Asn-Val-Ile-Gln-Ile-Ser-Asn-Asp-Leu-Glu-Asn-Leu-Arg), GR 83074 (Boc-Arg-Ala- DTφ-Phe-DPro-Pro-Nle-NH 2 ), Tyr-W-MIF-1 (Tyr-Pro-Tφ-Gly-NH 2 ), parathyroid hormone related peptide (107-111) (Thr-Arg-Ser-Ala-Tφ), angiotensinogen (1-14) Asp- Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Asn, Leupeptin (Ac-Leu-Leu-Arg- CHO), and any modified or truncated analogue thereof. 25. A peptide conjugate according to any of the previous claims wherein the conjugate is H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg- Lys-Leu-Leu-Gln-Asp-Ue-Met-Ser Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala- Arg-Ala-Arg-Leu-Lys6-NH2 (GHRH(1 -44)(Human)-Lys6-NH2); H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg- Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala- Arg-Ala-Arg-Leu-Glu6-NH2 (GHRH (l-44)(Human)-Glu6-NH2); H- Lys 6 .Ser-Val-Ser-Glu-Ue-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met- Glu-Arg-Val-Glu-Tφ-Leu-Arg-Lys-Lys-Leu-Gln-Asp- Val-His-Asn-Phe-OH (Lys6-PTH( 1 - 34)(Human)-OH); H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu- Arg- Val-Glu-Tφ-Leu-Arg-Lys-Lys-Leu-Gln- Asp- Val-His- Asn-Phe-Lys6-OH (PTH( 1 - 34)(Human)-Lys6-OH); H-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys- Glu-Phe-Ile-Ala-Tφ-Leu-Val-Lys-Gly-Arg-Lys6-OH (GLP- 1 -(7-36)(Human)-Lys6-OH); H-Gly-Gly-Thr-Tyr-Ser-Cys(Acm)-His-Phe-Gly-Pro-Leu-Thr-Tφ-Val-Cvs(Acm)-Lys-Pro- Gln-Gly-Gly-Lys6-OH (EMP- 1 -Lys6-OH); H- Lys6-Gly-Gly-Thr-Tyr-Ser-Cys(Acm)-His-Phe-Gly-Pro-Leu-Thr-Tφ-Val-Cys(Acm)- Lys-Pro-Gln-Gly-Gly-OH (Lys6-EMP- 1 -OH); H- Lys6-Gly-Gly-Thr-Tyr-Ser-Cys(Acm)-His-Phe-Gly-Pro-Leu-Thr-Tφ-Val-Cys(Acm)- Lys-Pro-Gln-Gly-Gly- Lys6-OH (Lys6-EMP-1- Lys6-OH); H-Aib-His-2-D-Nal-D-Phe-Lys-(Lys)6-NH2 (GHRP-(Lys)6-NH2); H-Tyr-Gly-Gly-Phe-Leu-Lys-Lys-Glu-Glu-Glu-Lys~OH (Leu-enkephalin-Lys-Lys-Glu- Glu-Glu-Lys-OH); H-Tyr-Gly-Gly-Phe-Leu-Lys-Glu-Glu-Glu-Glu-Lys-OH (Leu-enkephalin-Lys-Glu-Glu- Glu-Glu-Lys-OH); H-Tyr-Gly-Gly-Phe-Leu-Lys-Glu-Glu-Glu-Glu-Lys~OH (Leu-enkephalin-(Lys-Glu) 3 ; H-Tyr-Gly-Gly-Phe-Leu-(Dpr)6-OH (Leu-enkephalin-(Dpr)6-OH); H-Lys 6 -Tyr-Gly-Gly-Phe-Leu-OH (H-Lys 6 -Leu-enkephalin); H-Tyr-Gly-Gly-Phe-Leu- Lys 6 -OH (H-Leu-enkephalin-Lys 6 ); H-Lys 6 -Tyr-Gly-Gly-Phe-Leu-Lys 6 -OH (H-Lys 6 -Leu-enkephalin-Lys 6 -OH); Glu-His-Tφ-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-(Lys) 6 -OH (GnRH-Lys 6 -OH); Glu-His-Tφ-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-(Lys-Glu) 3 -OH (GnRH-(Lys-Glu) 3 -OH); and H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu- Arg-Val-Glu-Tφ-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-(Lys-Glu) 3 -OH (PTH 1-34 human-(Lys-Glu) 3 -OH). 26. A method for the preparation of a pharmacologically active peptide conjugate (X-Z) as defined in claim 2, comprising the steps of: a) coupling an N-α-protected amino acid or N-α-protected dipeptide in the carboxyl activated form, in the C-terminal activated form to an immobilised peptide sequence H-Z- SSM, thereby forming an immobilised N-α-protected peptide fragment, b) removing the N-α-protecting group, thereby forming an immobilised peptide fragment having an unprotected N-terminal end, c) coupling an additional N-α-protected amino acid in the carboxyl activated form, or an additional N-α-protected dipeptide in the C-terminal activated form to the N-terminal end of the immobilised peptide fragment, and repeating the removal/coupling step procedure in step b) and c) until the desired peptide sequence X is obtained, and then d) cleaving off the peptide conjugate from the solid support material. 27. A method for the preparation of a pharmacologically active peptide conjugate (Z-X) as defined in claim 3, comprising the steps of: a) coupling an N-α-protected amino acid, or an N-α-protected dipeptide to a solid support material (SSM), thereby forming an immobilised N-α-protected amino acid, b) removing the N-α-protecting group, thereby forming an immobilised amino acid or peptide fragment having an unprotected N-terminal end, c) coupling an additional N-α-protected amino acid in the carboxyl activated form, or an additional N-α-protected dipeptide in the C-terminal activated form to the N-terminal end of the immobilised amino acid or peptide fragment, and repeating the removal/coupling step procedure in step b) and c) until the desired peptide sequence X is obtained, d) coupling an additional N-α-protected amino acid in the carboxyl activated form, or an additional N-α-protected dipeptide in the C-terminal activated form to the N-terminal end of the immobilised peptide fragment, and repeating the removal/coupling step procedure in step b) and d) until the desired peptide sequence Z is obtained, and then e) cleaving off the peptide conjugate from the solid support material. 28. A method for the preparation of a pharmacologically active peptide conjugate (Z-X-Z) as defined in claim 4, comprising the steps of: a) coupling an N-α-protected amino acid in the carboxyl activated form, or an N-α- protected dipeptide in the C-terminal activated form to an immobilised peptide sequence H- Z-SSM, thereby forming an immobilised N-α-protected peptide fragment, b) removing the N-α-protecting group, thereby forming an immobilised peptide fragment having an unprotected N-terminal end, c) coupling an additional N-α-protected amino acid in the carboxyl activated form, or an additional N-α-protected dipeptide in the C-terminal activated form to the N-terminal end of the immobilised peptide fragment, and repeating the removal/coupling step procedure in step b) and c) until the desired peptide sequence X is obtained, and then d) coupling an additional N-α-protected amino acid in the carboxyl activated form, or an additional N-α-protected dipeptide in the C-terminal activated form to the N-terminal end of the immobilised peptide fragment, and repeating the removal/coupling step procedure in step b) and d) until the desired peptide sequence Z is obtained, and then e) cleaving off the peptide conjugate from the solid support material. 29. A method for producing the peptide conjugate of claim 1, comprising a) introducing a nucleic acid sequence encoding said conjugate into a host cell; b) culturing said host cell and c) isolating said conjugate from the culture. 30. A method for producing the peptide conjugate of claim 1 , comprising a) culturing a recombinant host cell comprising a nucleic acid sequence encoding said conjugate under conditions permitting the production of said conjugate; and b) isolating said conjugate from the culture. 31. The method according to claim 29 or claim 30, wherein the nucleic acid sequence encoding said conjugate is contained within a nucleic acid construct or a vector. 32. A composition comprising a pharmacologically active peptide conjugate as defined in any of the claims 1-25, and a pharmaceutical acceptable carrier. 33. A composition comprising H-Tφ-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu-(Lys-Glu) 3 -OH, H-Tφ-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu-(Glu) 6 -OH, H-Tyr-Gly-Gly-Phe-Leu-(Glu) 6 -OH or H-Tyr-Gly-Gly-Phe-Leu-(Lys) 6 -OH, and a pharmaceutical acceptable carrier. 34. A pharmacologically active peptide conjugate as defined in any of claims 1-26 for use in therapy. 35. A pharmacologically active peptide conjugate selected from the group consisting of H-Tφ-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu-(Lys-Glu) 3 -OH, H-Tφ-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu-(Glu) 6 -OH, H-Tyr-Gly-Gly-Phe-Leu-(Glu) 6 -OH and H-Tyr-Gly-Gly-Phe-Leu-(Lys) 6 -OH, for use in therapy. 36. Use of a pharmacologically active peptide conjugate as defined in any of claims 1-25 for the manufacture of a pharmaceutical composition for use in treatment of pain, HIV, cancer, diabetes, incontinence, hypertension, amnesia, Alzheimer's disease, fever, depression, sex hormone regulation, eating, schizophrenia, osteoporosis and insomnia. 37. A method for inhibiting neurons from transmitting pain impulses to the spinal cord, comprising administering to a subject in need thereof a conjugate comprising enkephalin and a stabilising sequence, Z of 4-20 amino acids covalently attached to X, wherein Z is selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His, Met, Orn, and amino acid units of the general formula I -NH-C(R')(R 2 )-C(=O)- (I) 1 wherein R and R are selected from the group consisting of hydrogen, Cι -6 -alkyl, phenyl, and phenyl-methyl, wherein Cι- -alkyl is optionally substituted with from one to three substituents selected from halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, and phenyl and phenyl-methyl is optionally substituted with from one to three substituents selected from Cι- -alkyl, C 2-6 -alkenyl, halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, or R 1 and R 2 together with the carbon atom to which they are bound form a cyclopentyl, cyclohexyl, or cycloheptyl ring, e.g. 2,4-diaminobutanoic acid and 2,3- diaminopropanoic acid; wherein the ratio between the half-life of said peptide conjugate and the half-life of enkephalin when treated with carboxypeptidase A or leucine aminopeptidase in about 50 mM phosphate buffer solution at about pH 7.4 at about 37°C or in serum or plasma is at least about 2, preferably at least about 3, such as at least about 5, more preferably at least about 7, such as at least about 9, e.g. at least about 10 or when X is inot orally absorbed said peptide conjugate is orally absorbed in an amount effective to inhibit neurons from transmitting pain impulses. 38. Use of a conjugate comprising enkephalin and a stabilising sequence, Z of 4-20 amino acids covalently attached to X, wherein Z is selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His, Met, Orn, and amino acid units of the general formula I -NH-C(R')(R 2 )-C(=O)- (I) wherein R and R are selected from the group consisting of hydrogen, Cι- -alkyl, phenyl, and phenyl-methyl, wherein Cι- -alkyl is optionally substituted with from one to three substituents selected from halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, and phenyl and phenyl-methyl is optionally substituted with from one to three substituents selected from Cι -6 -alkyl, C 2-6 -alkenyl, halogen, hydroxy, amino, cyano, nitro, sulfono, and 1 "? carboxy, or R and R together with the carbon atom to which they are bound form a cyclopentyl, cyclohexyl, or cycloheptyl ring, e.g. 2,4-diaminobutanoic acid and 2,3- diaminopropanoic acid; and Wherein the ratio between the half-life of said peptide conjugate and the half-life of enkephalin when treated with carboxypeptidase A or leucine aminopeptidase in about 50 mM phosphate buffer solution at about pH 7.4 at about 37°C or in serum or plasma is at least about 2, preferably at least about 3, such as at least about 5, more preferably at least about 7, such as at least about 9, e.g. at least about 10 or when X is inot orally absorbed said peptide conjugate is orally absorbedfor the manufacture of a pharmaceutical composition for use in treatment of pain. 39. A method for stimulating the release of growth hormone from the pituitary comprising administering to a subject in need thereof a conjugate comprising growth hormone releasing hormone or growth hormone releasing peptide and a stabilising sequence, Z of 4-20 amino acids covalently attached to X, wherein Z is selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His, Met, Orn, and amino acid units of the general formula I -NH-C(R')(R 2 )-C(=O)- (I) wherein R 1 and R 2 are selected from the group consisting of hydrogen, C] -6 -alkyl, phenyl, and phenyl-methyl, wherein Cι -6 -alkyl is optionally substituted with from one to three substituents selected from halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, and phenyl and phenyl-methyl is optionally substituted with from one to three substituents selected from Cι -6 -alkyl, C 2- -alkenyl, halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, or R 1 and R 2 together with the carbon atom to which they are bound form a cyclopentyl, cyclohexyl, or cycloheptyl ring, e.g. 2,4-diaminobutanoic acid and 2,3- diaminopropanoic acid; and Wherein the ratio between the half-life of said peptide conjugate and the half-life of growth hormone releasing hormone or growth hormone releasing peptide when treated with carboxypeptidase A or leucine aminopeptidase in about 50 mM phosphate buffer solution at about pH 7.4 at about 37°C or in serum or plasma is at least about 2, preferably at least about 3, such as at least about 5, more preferably at least about 7, such as at least about 9, e.g. at least about 10 or when X is inot orally absorbed said peptide conjugate is orally absorbedin an amount effective to stimulate the release of growth hormone. 40. Use of a conjugate comprising growth hormone releasing hormone or growth hormone releasing peptide and a stabilising sequence, Z of 4-20 amino acids covalently attached to X, wherein Z is selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His, Met, Orn, and amino acid units of the general formula I -NH-C(R J )(R 2 )-C(=O)- (I) wherein R 1 and R 2 are selected from the group consisting of hydrogen, Cι -6 -alkyl, phenyl, and phenyl-methyl, wherein Cj. 6 -alkyl is optionally substituted with from one to three substituents selected from halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, and phenyl and phenyl-methyl is optionally substituted with from one to three substituents selected from Cι -6 -alkyl, C 2- -alkenyl, halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, or R 1 and R 2 together with the carbon atom to which they are bound form a cyclopentyl, cyclohexyl, or cycloheptyl ring, e.g. 2,4-diaminobutanoic acid and 2,3- diaminopropanoic acid; and wherein the ratio between the half-life of said peptide conjugate and the half-life of growth hormone releasing hormone or growth hormone releasing peptide when treated with carboxypeptidase A or leucine aminopeptidase in about 50 mM phosphate buffer solution at about pH 7.4 at about 37°C or in serum or plasma is at least about 2, preferably at least about 3, such as at least about 5, more preferably at least about 7, such as at least about 9, e.g. at least about 10 or when X is not orally absorbed, said peptide conjugate is orally absorbed, for the manufacture of a pharmaceutical composition for use in stimulating the release of growth hormone. 41. A method for increasing hemoglobin levels comprising administering to a subject in need thereof a conjugate comprising EMP-1 and a stabilising sequence, Z of 4-20 amino acids covalently attached to X, wherein Z is selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His, Met, Orn, and amino acid units of the general formula I -NH-C(R 1 )(R 2 )-C(=O)- (I) wherein R 1 and R 2 are selected from the group consisting of hydrogen, Cι -6 - alkyl, phenyl, and phenyl-methyl, wherein Cι -6 -alkyl is optionally substituted with from one to three substituents selected from halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, and phenyl and phenyl-methyl is optionally substituted with from one to three substituents selected from Cι -6 -alkyl, C 2-6 -alkenyl, halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, or R 1 and R 2 together with the carbon atom to which they are bound form a cyclopentyl, cyclohexyl, or cycloheptyl ring, e.g. 2,4-diaminobutanoic acid and 2,3- diaminopropanoic acid; and Wherein the ratio between the half-life of said peptide conjugate and the half-life of EMP-1 when treated with carboxypeptidase A or leucine aminopeptidase in about 50 mM phosphate buffer solution at about pH 7.4 at about 37°C or in serum or plasma is at least about 2, preferably at least about 3, such as at least about 5, more preferably at least about 7, such as at least about 9, e.g. at least about 10 or when X is not orally absorbed said peptide conjugate is orally absorbed in an amount effective to increase hemoglobin levels. 42. Use of a conjugate comprising EMP-1 and a stabilising sequence, Z of 4-20 amino acids covalently attached to X, wherein Z is selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His, Met, Orn, and amino acid units of the general formula I -NH-C(R')(R 2 )-C(= O)- (I) wherein R and R are selected from the group consisting of hydrogen, C 1-6 -alkyl, phenyl, and phenyl-methyl, wherein Cι -6 -alkyl is optionally substituted with from one to three substituents selected from halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, and phenyl and phenyl-methyl is optionally substituted with from one to three substituents selected from Cj -6 -alkyl, C - -alkenyl, halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, or R 1 and R 2 together with the carbon atom to which they are bound form a cyclopentyl, cyclohexyl, or cycloheptyl ring, e.g. 2,4-diaminobutanoic acid and 2,3- diaminopropanoic acid; wherein the ratio between the half-life of said peptide conjugate and the half-life of EMP-1 when treated with carboxypeptidase A or leucine aminopeptidase in about 50 mM phosphate buffer solution at about pH 7.4 at about 37°C or in serum or plasma is at least about 2, preferably at least about 3, such as at least about 5, more preferably at least about 7, such as at least about 9, e.g. at least about 10 or when X is not orally absorbed said peptide conjugate is orally absorbed for the manufacture of a pharmaceutical composition for use in treating anemia by increasing hemoglobin levels. 43. A method for preventing or treating bone loss by altering the balance between ostoclastic and osteoblast activity comprising administering to a patient in need thereof a conjugate comprising parathyroid hormone and a stabilising sequence, Z of 4-20 amino acids covalently attached to X, wherein Z is selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His, Met, Orn, and amino acid units of the general formula I -NH-C(R')(R 2 )-C(-O)- (I) wherein R 1 and R 2 are selected from the group consisting of hydrogen, C 1- -alkyl, phenyl, and phenyl-methyl, wherein C 1-6 -alkyl is optionally substituted with from one to three substituents selected from halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, and phenyl and phenyl-methyl is optionally substituted with from one to three substituents selected from Cι -6 -alkyl, C 2-6 -alkenyl, halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, or R 1 and R 2 together with the carbon atom to which they are bound form a cyclopentyl, cyclohexyl, or cycloheptyl ring, e.g. 2,4-diaminobutanoic acid and 2,3- diaminopropanoic acid; and Wherein the ratio between the half-life of said peptide conjugate and the half-life of parathyroid hormone when treated with carboxypeptidase A or leucine aminopeptidase in about 50 mM phosphate buffer solution at about pH 7.4 at about 37°C or in serum or plasma is at least about 2, preferably at least about 3, such as at least about 5, more preferably at least about 7, such as at least about 9, e.g. at least about 10 or when X is not orally absorbed said peptide conjugate is orally absorbed in an amount effective to treat or prevent bone loss. 44. Use of a conjugate comprising parathyroid hormone and a stabilising sequence, Z of 4- 20 amino acids covalently attached to X, wherein Z is selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His, Met, Orn, and amino acid units of the general formula I -NH-C(R')(R 2 )-C(= O)- (I) wherein R 1 and R 2 are selected from the group consisting of hydrogen, C 1- -alkyl, phenyl, and phenyl-methyl, wherein C 1-6 -alkyl is optionally substituted with from one to three substituents selected from halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, and phenyl and phenyl-methyl is optionally substituted with from one to three substituents selected from Cι -6 -alkyl, C 2- -alkenyl, halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, or R 1 and R 2 together with the carbon atom to which they are bound form a cyclopentyl, cyclohexyl, or cycloheptyl ring, e.g. 2,4-diaminobutanoic acid and 2,3- 5 diaminopropanoic acid; and Wherein the ratio between the half-life of said peptide conjugate and the half-life of parathyroid hormone when treated with carboxypeptidase A or leucine aminopeptidase in about 50 mM phosphate buffer solution at about pH 7.4 at about 37°C or in serum or plasma 10 is at least about 2, preferably at least about 3, such as at least about 5, more preferably at least about 7, such as at least about 9, e.g. at least about 10, or when X is not orally absorbed said peptide conjugate is orally absorbed, for the manufacture of a pharmaceutical composition for use in preventing or treating osteoporosis. 1 5 45. A method for reducing blood glucose levels comprising administering to a subject in need thereof a conjugate comprising glucagon-like peptide- 1 and a stabilising sequence, Z of 4-20 amino acids covalently attached to X, wherein Z is selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His, Met, Orn, and amino acid units of the general formula I 0 -NH-C(R 1 )(R 2 )-C(=O)- (I) wherein R and R are selected from the group consisting of hydrogen, Cι- 6 -alkyl, phenyl, and phenyl-methyl, wherein C 1-6 -alkyl is optionally substituted with from one to three 5 substituents selected from halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, and phenyl and phenyl-methyl is optionally substituted with from one to three substituents selected from Cι -6 -alkyl, C -6 -alkenyl, halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, or R 1 and R 2 together with the carbon atom to which they are bound form a cyclopentyl, cyclohexyl, or cycloheptyl ring, e.g. 2,4-diaminobutanoic acid and 2,3- 0 diaminopropanoic acid; and wherein the ratio between the half-life of said peptide conjugate and the half-life of glucagon-like peptide- 1 when treated with carboxypeptidase A or leucine aminopeptidase in about 50 mM phosphate buffer solution at about pH 7.4 at about 37°C or in serum or plasma is at least about 2, preferably at least about 3, such as at least about 5, more preferably at least about 7, such as at least about 9, e.g. at least about 10 or when X is not orally absorbed said peptide conjugate is orally absorbed in an amount effective to reduce blood glucose levels. 46. Use of a conjugate comprising glucagon-like peptide- 1 and a stabilising sequence, Z of 4-20 amino acids covalently attached to X, wherein Z is selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His, Met, Orn, and amino acid units of the general formula I -NH-C(R')(R 2 )-C(=O)- (I) wherein R 1 and R 2 are selected from the group consisting of hydrogen, Cι -6 -alkyl, phenyl, and phenyl-methyl, wherein Cι -6 -alkyl is optionally substituted with from one to three substituents selected from halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, and phenyl and phenyl-methyl is optionally substituted with from one to three substituents selected from Cι- -alkyl, C 2-6 -alkenyl, halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, or R 1 and R 2 together with the carbon atom to which they are bound form a cyclopentyl, cyclohexyl, or cycloheptyl ring, e.g. 2,4-diaminobutanoic acid and 2,3- diaminopropanoic acid; and wherein the ratio between the half-life of said peptide conjugate and the half-life of glucagon-like peptide- 1 when treated with carboxypeptidase A or leucine aminopeptidase in about 50 mM phosphate buffer solution at about pH 7.4 at about 37°C or in serum or plasma is at least about 2, preferably at least about 3, such as at least about 5, more preferably at least about 7, such as at least about 9, e.g. at least about 10 or when X is not orally absorbed said peptide conjugate is orally absorbed, for the manufacture of a pharmaceutical composition for use in treatment of diabetes. 47. A method for regulating production of sex hormones comprising administering to a subject in need thereof a conjugate comprising gonadotropin releasing hormone and a stabilising sequence, Z of 4-20 amino acids covalently attached to X, wherein Z is selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His, Met, Orn, and amino acid units of the general formula I -NH-C(R')(R 2 )-C(= O)- (I) wherein R and R are selected from the group consisting of hydrogen, Cι- -alkyl, phenyl, and phenyl-methyl, wherein Cj- -alkyl is optionally substituted with from one to three substituents selected from halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, and phenyl and phenyl-methyl is optionally substituted with from one to three substituents selected from Cι- -alkyl, C 2-6 -alkenyl, halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, or R and R together with the carbon atom to which they are bound form a cyclopentyl, cyclohexyl, or cycloheptyl ring, e.g. 2,4-diaminobutanoic acid and 2,3- diaminopropanoic acid; and wherein the ratio between the half-life of said peptide conjugate and the half-life of gonadotropin when treated with carboxypeptidase A or leucine aminopeptidase in about 50 mM phosphate buffer solution at about pH 7.4 at about 37°C or in serum or plasma is at least about 2, preferably at least about 3, such as at least about 5, more preferably at least about 7, such as at least about 9, e.g. at least about 10 or when X is not orally absorbed said peptide conjugate is orally absorbed in an amount effective to regulate production of sex hormones. 48. Use of a conjugate comprising gonadotropin releasing hormone and a stabilising sequence, Z of 4-20 amino acids covalently attached to X, wherein Z is selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His, Met, Orn, and amino acid units of the general formula I -NH-C(R 1 )(R 2 )-C(=O)- (I) wherein R 1 and R 2 are selected from the group consisting of hydrogen, Cι- -alkyl, phenyl, and phenyl-methyl, wherein Cι -6 -alkyl is optionally substituted with from one to three substituents selected from halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, and phenyl and phenyl-methyl is optionally substituted with from one to three substituents selected from Cι -6 -alkyl, C -6 -alkenyl, halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, or R 1 and R 2 together with the carbon atom to which they are bound form a cyclopentyl, cyclohexyl, or cycloheptyl ring, e.g. 2,4-diaminobutanoic acid and 2,3- diaminopropanoic acid; and wherein the ratio between the half-life of said peptide conjugate and the half-life of gonadotropin releasing hormone when treated with carboxypeptidase A or leucine aminopeptidase in about 50 mM phosphate buffer solution at about pH 7.4 at about 37°C or in serum or plasma is at least about 2, preferably at least about 3, such as at least about 5, more preferably at least about 7, such as at least about 9, e.g. at least about 10 or when X is not orally absorbed said peptide conjugate is orally absorbed and the ratio between the half- life of said peptide conjugate for the manufacture of a pharmaceutical composition for use in regulating the level of sex homones. 49. A method for treating sleep disorders comprising administering to a subject in need thereof a conjugate comprising delta sleep inducing peptide and a stabilising probe, Z of 4- 20 amino acids covalently attached to X, wherein Z is selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His, Met, Orn, and amino acid units of the general formula I -NH-C(R 1 )(R 2 )-C(= O)- (I) wherein R and R are selected from the group consisting of hydrogen, Cj- 6 -alkyl, phenyl, and phenyl-methyl, wherein Cι -6 -alkyl is optionally substituted with from one to three substituents selected from halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, and phenyl and phenyl-methyl is optionally substituted with from one to three substituents selected from Cι- -alkyl, C 2- -alkenyl, halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, or R 1 and R 2 together with the carbon atom to which they are bound form a cyclopentyl, cyclohexyl, or cycloheptyl ring, e.g. 2,4-diaminobutanoic acid and 2,3- diaminopropanoic acid; and wherein the ratio between the half-life of said peptide conjugate and the half-life of delta- sleep inducing peptide when treated with carboxypeptidase A or leucine aminopeptidase in about 50 mM phosphate buffer solution at about pH 7.4 at about 37°C or in serum or plasma is at least about 2, preferably at least about 3, such as at least about 5, more preferably at least about 7, such as at least about 9, e.g. at least about 10, or when the pharmacologically active peptide X is not orally absorbed, the conjugate will be orally absorbed, in an amount effective to treat said sleep disorder. 50. Use of a conjugate comprising delta-sleep inducing peptide and a stabilising probe, Z of 4-20 amino acids covalently attached to X, wherein Z is selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His, Met, Orn, and amino acid units of the general formula I -NH-C(R 1 )(R 2 )-C(=O)- (I) wherein R 1 and R 2 are selected from the group consisting of hydrogen, C 1-6 - alkyl, phenyl, and phenyl-methyl, wherein Cι -6 -alkyl is optionally substituted with from one to three substituents selected from halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, and phenyl and phenyl-methyl is optionally substituted with from one to three substituents selected from C 1-6 -alkyl, C 2 . 6 -alkenyl, halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, or R 1 and R 2 together with the carbon atom to which they are bound form a cyclopentyl, cyclohexyl, or cycloheptyl ring, e.g. 2,4-diaminobutanoic acid and 2,3- diaminopropanoic acid; and wherein the ratio between the half-life of said peptide conjugate and the half-life of Substance P when treated with carboxypeptidase A or leucine aminopeptidase in about 50 mM phosphate buffer solution at about pH 7.4 at about 37°C and in serum or plasma is at least about 2, preferably at least about 3, such as at least about 5, more preferably at least about 7, such as at least about 9, e.g. at least about 10, or when the pharmacologically active peptide X is not orally absorbed, the conjugate will be orally absorbed, for the manufacture of a pharmaceutical composition for use in treating a sleep disorder 51. Use of a stabilising peptide sequence (Z) of 4-20 amino acid units for the preparation of a pharmacologically active peptide conjugate as defined in any of claims 1-26, each amino acid unit in said stabilising peptide sequence Z being independently selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His, Met, Orn, or amino acid units of the general formula I -NH-C(R')(R 2 )-C(= O)- (I) 1 wherein R and R independently are selected from hydrogen, Cj -6 -alkyl, phenyl, and phenyl-methyl, wherein Cι- -alkyl is optionally substituted with from one to three substituents selected from halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, and phenyl and phenyl-methyl is optionally substituted with from one to three substituents selected from Cj -6 -alkyl, C -6 -alkenyl, halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, or R and R together with the carbon atom to which they are bound form a cyclopentyl, cyclohexyl, or cycloheptyl ring; or a salt thereof.

Inventors: LARSEN BJARNE DUE, LARSEN, BJARNE, DUE
Applicants: LARSEN BJARNE DUE, ZEALAND PHARMACEUTICALS A S, LARSEN, BJARNE, DUE, ZEALAND PHARMACEUTICALS A/S
Application year: 1999
Main classification: C07K1
IPC codes: A61K38, A61K47, A61P3, A61P5, A61P9, A61P13, A61P19, A61P25, A61P29, A61P31, A61P35, C07K1, C07K5, C07K7, C07K14, C12N15, C12P21