SYNTHETIC PEPTIDES HAVING PITUITARY GROWTH HORMONE RELEASING ACTIVITY

Abstract: Novel peptides having the following amino acid se­ quence X-Y₁-Z₁-E₁-G₁-J₁-Q (I) X-Y₂-Z₂-E₂-G₂-J₂-Q (II) X-Y₃-Z₃-E₃-G₃-J₃-Q (III) X-Y₄-Z₄-E₄-Q (IV) X-Y₅-Z₅-E₅-J₅-Q (V) X-Y₆-Z₆-E₆-J₆-Q (VI) X-Y₇-Z₇-E₇-G₇-J₇-Q (VII) X-Y₈-Z₈-E₈-G₈-Q (VIII) X-Y₉-Z₉-E₉-G₉-J₉-Q (IX) X′-Y₁₀-Z₁₀-E₁₀-G₁₀-J₁₀-L₁₀-Q (X) and the pharmaceutically acceptable salts thereof, wherein X is selected from a group consisting of -NH₂, -NHCH₃, and -N(CH₃)₂; Y₁, G₁, Y₂, G₂, E₄, Z₅, J₅, Y₆, G₆, Z₇, G₇, Y₈, G₈, Y₉, Y₁₀ and G₁₀ are selected from a group consisting of tyrosine tryp­ tophan, and phenylalanine; Z₁, J₁, Z₂, Z₃, E₃, Y₄, Z₄, E₅, G₅, E₆, J₆, Y₇, E₇, Z₈, E₈, E₈, Z₉, E₉, Z₁₀ and J₁₀ are selected from a group consisting of D-tyrosine, D-tryptophan, and D-phenylalanine; J₃ and Z₆ are selected from a group consisting of glycine, alanine, valine, leucine, isoleucine, proline, hy­ droxyproline, serine, threonine, cysteine and methionine; E₁ is selected from a group consisting of glycine, alanine, valine, leucine, isoleucine, proline, hydroxyproline, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, and histidine; E₂ is selected from a group consisting of glycine, alanine, valine, leucine, methionine, and isoleucine; J₂ is selected from a group consisting of glycine, alanine, D-alanine, valine, D-valine, leucine, D-leucine, iso­ leucine, D-isoleucine, proline, D-proline, hydroxyproline, D-hydroxyproline, serine, D-serine, threonine, D-threonine, cysteine, D-cysteine, methionine, and D-methionine; Y₃ is selected from a group consisting of tyrosine, D-tyrosine, tryptophan, D-tryptophan phenylalanine, and D-phenylalanine; G₃ is selected from a group consisting of lysine and arginine; Y₅ is selected from a group consisting of D-lysine and D-arginine; J₇ is selected from a group consisting of glycine, alanine, valine, leucine, isoleucine, proline, hydroxypro­ line, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, and lysine;

Description: SYNTHETIC PEPTIDES HAVING PITUITARY GROWTE HORMONE RELEASING ACTIVITY Background of the Invention 1. Field of the Invention This invention relates to peptides which possess pituitary growth hormone releasing activity. 2. Description of the Prior Art Growth hormone, which is secreted from the -pituitary, causes growth of all tissues of the body that are capable of growing. In addition; growth hormone is known to have the following basic effects on the metabolic process of the body: .1. Increased rate of protein synthesis in all cells of the body; 2. Decreased rate of carbohydrate utilization in cells of the body; 3. Increased mobilization of free fatty acids and use of fatty acids for energy. A deficiency in growth hormone secretion can result in various medical disorders, such as some instances of dwarfism. Various ways are known to release growth hormone. For example, chemicals such as arginine, L-dihydroxyphenylamine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalmus perhaps either to decrease somatostatin secretion or to increase an unknown endogenous growth hormone-releasing hormone or both. Compounds which directly act on the pituitary to release growth hormone include prostaglandin E1 and E2, theophylline, and cyclicnuclectides. Howevor, these compounds neither specifically release growth hormone nor are they believed to act at the putative growth hormone-releasing hormone receptors in the peripheral membrane of the pituitary cell to initiate growth hormone release. In addition, under special conditions certain chemically defined peptides, e.g., vasopressin, thyroid-releasing hormone (TRH), luteinizing hormonereleasing hormone (LH-RH), a-melanocyte-stimulating hormone (-MSH), glucagon, substance P, neurotensin; Met-enkephelin, a-endorphin, cholera-enderotoxin, and basic myelin protein, act to release growth hormone from the pituitary. However, only TRH acts directly on the pituitary to elicit this response. -Furthermore, the above listed peptides release other pituitary hormones and under most experimental conditions do not release growth hormone. For example, TRH does not release growth hormone in normal rats or in normal humans or from pituitaries of normal rats or monkeys. In vitro, TRH releases growth hormone, prolactin, and thyroid stimulating hormone (TSH) and in vivo TRH releases these hormones from bovine pituitary. Vasopressin's induced release of growth hormone is considered to be due to a non-specific response to stress caused by administration of high dosages of vasopressin. Accordingly it would be highly desirable to have a compound which directly acts on the pituitary under normal experimental conditions to effect the release of growth hormone therefrom. Such peptides would be useful in vitro as unique research tools for understanding how growth hormone secretion is regulated at the pituitary level and would also be useful in vivo to treat symptoms related to growth hormone defici encies. Summary of the Invention In accordance with the present invention there is provided peptides which act directly on the pituitary under normal experimetal conditions in vitro to release growth hormone therefrom. These growth hormone releasing peptides can be utilized in vitro as unique research tools for understanding, inter alia, how growth hormone secretion is regulated at the pituitary level. Also, the growth hormone releasing peptides of the instant invention can also be administered in vivo to increase growth hormone release. More particularly, this invention encompasses novel peptides having -a formula selected from a group consisting of X-Y1-Z1-E1-G1-J1-Q (I) X-Y2-Z2-E2-G2-J2-Q (II) X-Y3-Z3-E3-G3-J3-Q (III) X-Y4-Z4-E4-Q (IV) X-Y5-Z5-E5-J5-Q (V) X-Y6-Z6-E6-J6-Q (VI) X-Y7-Z7-E7-G7-J7-Q (VII) X-Y8-Z8-E8-G8-Q (VIII) X-Y9-Z9-E9-G9-J9-Q (IX) X'-Y10-Z10-E10-G10-J10-L10-Q (X) and the pharmaceutically acceptable salts thereof, wherein X is selected from a group consisting of -NH2, -NHCH3, and -N(CH3)2; Y1, G1, Y2, G2, E4, Z5, J5, Y6, G6, Z7, G7, Y8, G8, Yg, Gg, Y10, and G10 are selected from a group consisting of tyrosine, tryptophan, and phenyl alanine; ; zl, J1' Z2, Z3, E3, Y4, Z4, E5, G5, E61 J6' Y7, E7, Zs, E8, Z9, E9, Z10, and J10 are selected from a group consisting of D-tyrosine, D-tryptophan, and D-phenylalanine; and Z6 are selected from a group consisting of glycine, alanine, valine, leucine, isoleucine, proline, hydroxyproline, serine, threonine, cysteine, and methionine; E1 is selected from a group consisting of glycine, alanine, valine, leucine, isoleucine, proline, hydroxyproline, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, and histidine; E2 is -selected from a group consisting; of glycine, alanine, valine, leucine, methionine, and isoleucine; J2 is selected from a group consisting of glycine, alanine, D-alanine, valine, D-valine, leucine, D-leucine, isoleucine, D-isoleucine, proline, D-proline, hydroxyproline, D-hydroxyproline, serine, D-serine, threonine, D-threonine, cysteine, D-cysteine, methionine, and D-methionine; Y3 is selected from a group conisting of tyrosine, D-tyrosine, tryptophan, D-tryptophan, phenylalanine, and D-phenylalanine; G3 is selected from a group consisting of lysine and arginine; Y5 is selected from a group consisting of D-lysine and D-arginine; J7 is selected from a group consisting of glycine, alanine, valine, leucine, isoleucine, proline, hydroxyproline, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, and lysine; ; Jg is selected from a group consisting of natural amino acids and the D-configuration thereof; X' is selected from a group consisting of -NHCHOCH3, NH2, -NHCH3, and -N(CH3)2; E10 is selected from a group consisting of glycine, alanine, valine, leucine, isoleucine, serine, threonine, methionine, asparagine, and glutamine; L10 is selected from a group consisting of asparagine, glutamine, glutamic acid, arginine, lysine, serine, and threonine; and Q is a C-terminal functional group selected from a group consisting of amide (-CONH2), amide lower alkyl (-NHR), amide (di(lower alkyl) (-CONR1R2), lower alkoxy (-CH2OR), hydroxy (-CH20H)/ carboxy (-COO) and the lower ester derivatives thereof (-COOR). Detailed Description of the Preferred Embodiments The peptides of this invention have an amino acid sequence selected from a group consisting of the formulae I-X, supra, and the pharmaceutically acceptable salts thereof. Preferably, the peptides of this invention have an amino acid sequence selected from the group consisting of the following formulae: X-Tyr-D-Trp-El-Trp-D-Phe-Q (XI) X-Trp-D-Phe-Ala-Tyr-J2-Q (XII) X-Y3-D-Phe-D-Phe-Lys-Met-Q (XIII) X-D-Trp-Z4-E4-Q (XIV) X-D-Lys-Tyr-D-Trp-D-Trp-Phe-Q (XV) X-Tyr-Gly-D-Trp-Phe-D-Phe-Q (XVI) X-D-Phe-Z7-E7-Phe-J7-Q (XVII) X-Y8-D-Trp-E8-G8-Q (XVIII A) X-Tyr-D-Trp-D-Trp--Tyr-Q (XVIII B) X-Yg-D-Trp-E9-G9-J9-Q (XIX) X'-Tyr-D-Trp-E10-Trp-D-Phe-l10-Q (XX) wherein X, X', Y8, Y9, , and Q are as defined above; E4, Z7, G8, and Gg are selected from the group consisting of tryptophan and phenylalanine; ; Z4, E7, E8, and Eg are selected from the group consisting of D-tryptophan and D-phenylalanine; E1 is selected from a group consisting of glycine, alanine, valine, leucine, isoleucine, serine, threonine, asparaginine, and glutamine; J2 is an amino acid residue selected from the group consisting of D-leucine and methionine; Y3 is an amino acid residue selected from a group consisting of tryptophan and D-tryptophan; J7 is selected from a group consisting' of lysine and methionine; Jg is selected from the group consisting of methionine, D-methionine, leucine, D-leucine, phenylalanine, D-phenylalanine, arginine, D-arginine, proline, and D-proline; E10 is selected from a group consisting of glycine, alanine, valine, leucine, isoleucine, serine, threonine, asparagine, and glutamine; and L10 is selected from the group consisting of arginine, lysine, asparagine, glutamine, serine, and threonine. More preferably, the peptides of this invention have the amino acid sequence selected from the group consisting of the following formulae: X'-Tyr-D-Trp-Ala-Trp-D-Phe-L10-Q (XXI) wherein X' and Q are as defined above; and L10 is selected from the group glutamine and. threonine. All amino acid residues identified herein are in the natural or L-configuration -unless otherwise specified. Abbreviations for amino acid residue have been used in accordance with the following standard peptide nomenclature: Tyr -L-tyrosine Ile -L-isoleucine D-Tyr -D-tyrosine D-Ile -D-isoleucine Gly -glycine Leu -L-leucine Phe -L-phenylalanine D-Leu -Dl eucine D-Phe -D-phenylalanine Thr -L-threonine Met -L-methionine D-Thr -D-threonine D-Met -D-methionine Val -L-valine Ala -L-alanine D-Val -D-valine D-Ala -D-alanine Pro -L-proline Ser -L-serine D-Pro -D-proline D-Ser -D-serine Gln -L-glutamine Lys -L-lysine D-Gln -D-glutamine D-Lys -D-lysine Glu -L-glutamic acid Asn -L-asparagine D-Glu -D-glutamic acid D-Asn -D-aspargine Trp -L-tryptophan His -L-histidine D-Trp -D-tryptophan D-His -D-histidine D-Asp -D-aspartic acid Cys -L-cysteine Arg -L-arginine D-Cys -D-cysteine D-Arg -D-arginine Dopa -L-dopamine < Glu -L-pyroglutamic acid D-Dopa -D-dopamine D- < Glu -D-pyroglutamic acid Hypro -L-hydroxroline D-Hypro -D-hydroxyproline The term "pharmaceutically acceptable salts," as used herein, refers to the non-toxic alkali metal, alkaline earth metal and ammonium salts commonly used in the pharmaceutical industry including the sodium, potassium, lithium, calcium, magnesium, barium, ammonium and protamine zinc salts which are prepared by methods well known in the art. The term also includes non-toxic acid addition salts which are generally prepared by reacting the compounds of this invention with a suitable organic or inorganic acid. Representative salts include the hydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate,- tartrate, napsylate, and the like. The term "lower alkyl',, as used herein, refers to straight and branched chain alkyl groups having from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, 1,2-dimethylbutyl, and ' the like. Preferably, the lower alkyl group is methyl or ethyl. The term "lower alkoxy", as used herein,' refers to straight and branched chain alkoxy groups having from 1 to 6 carbon atoms, such as methoxy, methoxy n-propoxy, iso-propoxy, n-butoxy tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy and the like. Preferably, the lower alkoxy group is methoxy or ethoxy. The term "lower ester derivative", as used herein, refers to straight and branched chain alkyl ester derivatives having from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, tertbutyl, sec-butyl, n-pentyl, n-hexyl, and 1,2-dimethyl butyl ester derivatives and the like. Preferably, the lower ester derivative is a methyl ester derivative or an ethyl ester derivative. Accordingly, each R, R1, and R2 of Q is selected from a group consisting of straight and branched chain alkyl groups containing 1-6 carbon atoms. Preferably, each R, R1, and R2 is selected from the group consisting of alkyl group containing 1-2 carbon atoms. Peptides within the scope of the instant invention include, but are not limited to, those set forth in Table I. TABLE I X-Tyr-D-Trp-Ala-Trp-D-Phe-Q X-Tyr-D-Trp-Ser-Trp-D-Phe-Q X-Tyr-D-Trp-Asn-Trp-D-Phe-Q X-Tyr-D-Trp-Gln-Trp-D-Phe-Q X-Tyr-D-Trp-Thr-Trp-D-Phe-Q X-Tyr-D-Trp-Gly-Trp-D-Phe-Q X-Trp-D-Phe-Ala-Tyr-D-Leu-Q X-Trp-D-Phe-Ala-Tyr-D-Leu-Q X-Trp-D-Phe-Ala-Tyr-Met-Q X-Trp-D-Phe-D-Phe-Lys-Met-Q X-D-Trp-D-Phe-D-Phe-Lys-Met-Q X-D-Trp-D-Trp-Trp-Q X-D-Trp-D-Trp-Phe-Q X-D-Trp-D-Phe-Trp-Q X-D-Trp-D-Phe-Phe-Q X-D-Lys-Tyr-D-Trp-D-Trp-Phe-CONH2 X-D-Lys-Tyr-D-Trp-D-Trp-Phe-CONHR X-D-Lys-Tyr-D-Trp-D-Trp-Phe-CONR1R2 X-D-Lys-Tyr-D-Trp-D-Trp-Phe-CH2OR X-D-Lys-Tyr-D-Trp-D-Trp-Phe-CH2OH X-D-Lys-Tyr-D-Trp-D-Trp-Phe-COON X-D-Lys-Tyr-D-Trp-D-Trp-Phe-COOR X-Tyr-Gly-D-Trp-Phe-D-Phe-CONH2 X-Tyr-Gly-D-Trp-Phe-D-Phe-CONHR <RTI ID=9.6> X-Tyr-Gly-D-Trp-Phe-D-Phe-CONR1R2 X-Tyr-Gly-D-Trp-Phe-D-Phe-CH2OR X-Tyr-Gly-D-Trp-Phe-D-Phe-CH2OH X-Tyr-Gly-D-Trp-Phe-D-Phe-COOH X-Tyr-Gly-D-Trp-Phe-D-Phe-COOR X-D-Phe-Trp-D-Trp-Phe-Lys-Q X-D-Phe-Trp-D-Trp-Phe-Met-Q X-D-Phe-Trp-D-Phe-Phe-Lys-Q X-D-Phe-Trp-D-Phe-Phe-Met-Q X-D-Phe-Phe-D-Trp-Phe-Lys-Q X-D-Phe-Phe-D-Trp-Phe-Met-Q X-D-Phe-Phe-D-Phe-Phe-Lys-Q X-D-Phe-Phe-D-Phe-Phe-Met-Q X-Tyr-D-Trp-D-Trp-Trp-Q X-Tyr-D-Trp-D-Trp-Phe-Q X-Tyr-D-Trp-D-Phe-Trp-Q X-Trp-D-Trp-D-Trp-Trp-Q X-Trp-D-Trp-D-Trp-Phe-Q X-Trp-D-Trp-D-PheTrp-Q X-Trp-D-Trp-D-Phe-Phe-Q X-Phe-D-Trp-D-Trp-Trp-Q X-Phe-D-Trp-D-Trp-Phe-Q X-Phe-D-Trp-D-Phe-Trp-Q X-Phe-D-Trp-D-Phe-Phe-Q X-Tyr-D-Trp-D-Trp-Tyr- CONH2 X-Tyr-D-Trp-D-Trp-Tyr-CONHR X-Tyr-D-Trp-D-Trp-Tyr- CONR1R2 X-Tyr-D-Trp-D-Trp-Tyr-CH2OR X-Tyr-D-Trp-D-Trp-Tyr-CH2OH X-Tyr-D-Trp-D-Trp-Tyr-COOH <RTI ID=10.3> X-Tyr-D-Trp -D-Trp -Tyr- COOR X-Tyr-D-Trp-D-Trp-Trp-Met-Q X-Tyr-D-Trp-D-Trp-Trp-D-Met-Q X-Tyr-D-Trp-D-Trp-Trp-Leu-Q X-Tyr-D-Trp-D-Trp-Trp-D-Leu-Q X-Tyr-D-Trp-D-Trp-Trp-Phe-Q X-Tyr-D-Trp-D-Trp-Trp-D-Phe-Q X-Tyr-D-Trp-D-Trp-Trp-Arg-Q X-Tyr-D-Trp-D-Trp-Trp-D-Arg-Q X-Tyr-D-Trp-D-Trp-Trp-Pro-Q X-Tyr-D-Trp-D-Trp-Trp-D-Pro-Q X-Tyr-D-Trp-D-Trp-Phe-Met-Q X-Tyr-D-Tr-D-Trp-Phe-D-Met-Q X-Tyr-D-Trp-D-Trp-Phe-Leu-Q X-Tyr-D-Trp-D-Trp-Phe-D-Leu-Q X-Tyr-D-Trp-D-Trp-Phe-Phe-Q X-Tyr-D-Trp-D-Trp-Phe-D-Phe-Q X-Tyr-D-Trp-D-Trp-Phe-Arg-Q X-Tyr-D-Trp-D-Trp-Phe-D-Arg-Q X-Tyr-D-Trp-D-Trp-Phe-Pro-Q X-Tyr-D-Trp-D-Trp-Phe-D-Pro-Q X-Tyr-D-Trp-D-Phe-Trp-Met-Q X-Tyr-D-Trp-D-Phe-Trp-D-Met-Q X-Tyr-D-Trp-D-Phe-Trp-Leu-Q X-Tyr-D-Trp-D-Phe-Trp-D-Leu-Q X-Tyr-D-Trp-D-Phe-Trp-Phe-Q <RTI ID=11.2> X-Tyr-D-Trp-D-Phe-Trp-D-Phe-a X-Tyr-D-Trp-D-Phe-Trp-Arg-Q X-Tyr-D-Trp-D-Phe-Trp-D-Arg-Q X-Tyr-D-Trp-D-Phe-Trp-Pro-Q X-Tyr-D-Trp-D-Phe-Trp-D-Prc-Q X-Tyr-D-Trp-D-Phe-Phe-Met-Q X-Tyr-D-Trp-D-Phe-Phe-D-Met-Q X-Tyr-D-Trp-D-Phe-Phe-Leu-Q X-Tyr-D-Trp-D-Phe-Phe-D-Leu-Q X-Tyr-D-Trp-D-Phe-Phe-Phe- Q X-Tyr-D-Trp-D-Phe-Phe-D-Phe-Q X-Tyr-D-Trp-D-Phe-Phe-Arg-Q X-Tyr-D-Trp-D-Phe-PheD-Arg-Q X-Tyr-D-Trp-D-Phe-Phe-Pro-Q X-Tyr-D-Trp-D-Phe-Phe-D-Pro-Q X-Trp-D-Trp-D-Trp-Trp-Met-Q X-Trp-D-Trp-D-Trp-Trp-D-Met-Q X-Trp-D-Trp-D-Trp-Trp-Leu-Q X-Trp-D-Trp-D-Trp-Trp-D-Leu-Q X-Trp-D-Trp-D-Trp-Trp-Phe-Q X-Trp-D-Trp-D-Trp-Trp-D-Phe-Q X-Trp-D-Trp-D-Trp-Trp-Arg-Q X-Trp-D-Trp-D-Trp-Trp-D-Arg-Q X-Trp-D-Trp-D-Trp-Trp-Pro-Q X-Trp-D-Trp-D-Trp-Trp-D-Pro-Q X-Trp-D-Trp-D-Trp-Phe-Met-Q X-Trp-D-Trp-D-Trp-Phe-D-Met-Q X-Trp-D-Trp-D-Trp-Phe-Leu-Q X-Trp-D-Trp-D-Trp-Phe-D-Leu-Q X-Trp-D-Trp-D-Trp-Phe-Phe-Q X-Trp-D-Trp-D-Trp-Phe-D-Phe-Q -Trp-D-Trp-D-Trp-Phe-Arg-Q X-Trp-D-Trp-D-Trp-Phe-D-Arg-Q X-Trp-D-Trp-D-Trp-Phe-Pro-Q X-Trp-D-Trp-D-Trp-Phe-D-Pro-Q X-Trp-D-Trp-D-Phe-Trp-Net-Q X-Trp-D-Trp-D-Phe-Trp-D-Met-Q X-Trp-D-Trp-D-Phe-Trp-Leu-Q X-Trp-D-Trp-D-Phe-Trp-D-Leu-Q X-Trp-D-Trp-D-Phe-Trp-Phe-Q X-Trp-D-Trp-D-Phe-Trp-D-Phe-Q X-Trp-D-Trp-D-Phe-Trp-Arg-Q X-Trp-D-Trp-D-Phe-Trp-D-Arg-Q X-Trp-D-Trp-D-Phe-Trp-Pro-Q X-Trp-D-Trp-D-Phe-TrpD-Pro-Q <RTI ID=12.4> X-Trp-D-Trp-D-Phe-Phe-Met-Q X-Trp-D-Trp-D-Phe-Phe-D-Met-Q X-Trp-D-Trp-D-Phe-Phe-Leu-Q X-Trp-D-Trp-D-Phe-Phe-D-Leu-Q X-Trp-D-Trp-D-Phe-Phe-Arg-Q X-Trp-D-Trp-D-Phe-Phe-D-Arg-Q X-Trp-D-Trp-D-Phe-Phe-Pro-Q X-Trp-D-Trp-D-Phe-Phe-D-Pro-Q X-Phe-D-Trp-D-Trp-Trp-Met-Q X-Phe-D-Trp-D-Trp-.Trp-D-Met-Q X-Phe-D-Trp-D-Trp-Trp-Leu-Q X-Phe-D-Trp-D-Trp-Trp-D-Leu-Q X-Phe-D-Trp-D-Trp-Trp-Phe-Q X-Phe-D-Trp-D-Trp-Trp-D-Phe-Q X-Phe-D-Trp-D-Trp-Trp-Arg-Q X-Phe-D-Trp-D-Trp-Trp-D-Arg-Q X-Phe-D-Trp-D-Trp-Trp-Pro-Q X-Phe-D-Trp-D-Trp-Trp-D-Pro-Q X-Phe-D-Trp-D-Trp-Phe-Met-Q X-Phe-D-Trp-D-Trp-Phe-D-Met-Q X-Phe-D-Trp-D-Trp-Phe-Leu-Q X-Phe-D-Trp-D-Trp-Phe-D-Leu-Q X-Phe-D-Trp-D-Trp-Phe-Phe-Q X-Phe-D-Trp-D-Trp-Phe-D-Phe-Q X-Phe-D-Trp-D-Trp-Phe-Arg-Q X-Phe-D-Trp-D-Trp-Phe-D-Arg-Q <RTI ID=13.2> X-Phe-D-rp-D-Trp-Phe-Pro-Q X-Phe-D-Trp-D-Trp-Phe-D-Pro-Q X-Phe-D-Trp-D-Phe-TrpMet-Q X-Phe-D-Trp-D-Phe-Trp-D-Met-Q X-Phe-D-Trp-D-Phe-Trp-Leu-Q X-Phe-D-Trp-D-Phe-Trp-Phe-Q X-Phe-D-Trp-D-Phe-Trp-D-Phe-Q -X-Phe-D-Trp-D-Phe-Trp-Arg-Q X-Phe-D-Trp-D-Phe-Trp-D-Arg-Q X-Phe-D-Trp-D-Phe-Trp-Pro-Q X-Phe-D-Trp-D-Phe-Trp-D-Pro-Q X-Phe-D-Trp-D-Phe-Phe-Met-Q X-Phe-D-Trp-D-Phe-Phe-D-Met-Q X-Phe-D-Trp-D-Phe-Phe-Leu-Q X-Phe-D-Trp-D-Phe-Phe-D-Leu-Q X-Phe-D-Trp-D-Phe-Phe-Phe-Q X-Phe-D-Trp-D-Phe-Phe-D-Phe-Q X-Phe-D-Trp-D-Phe-Phe-Arg-Q X-Phe-D-Trp-D-Phe-Phe-D-Arg-Q X-Phe-D-Trp-D-Phe-Phe-Pro-Q X-Phe-D-Trp-D-Phe-Phe-D-Pro-Q X' -Tyr-D-Trp-Ala-Trp-D-Phe-Gln-Q X'-Tyr-D-Trp-Gly-Trp-D-Phe-Gln-Q X' -Tyr-D-Trp-Ala-Trp-D-Phe-Thr-Q X'-Phe-D-Phe-Ser-Phe-D-Phe-Asn-Q X'-Trp-D-Tyr-Met-Tyr-D-Trp-Ser-Q X' -Tyr-D-Trp-Asp-Trp-D-Tyr-Lys-Q X'-Trp-D-Trp-Val-Trp-D-Trp-Glu-Q X'-Tyr-D-Tyr-Leu-Trp-D-Trp-Arg-Q X'-Phe-D-Trp-Ile-Trp-D-Phe-Gln-Q X'-Tyr-D-Phe-Ala-Phe-D-Phe-Arg-Q X' -Tyr-D-Trp-Gly-Trp-D-Tyr-Thr-Q X' -Tyr-D-Tyr-Val-Tyr-D-Phe-Glu-Q X'-Trp-D-Trp-Leu-Trp-D-Phe-Asn-Q X' -Tyr-D-Trp-Ile-Trp-D-Trp-Lys-Q X'-Tyr-D-Trp-Ala-Trp-D-Phe-Asn-Q X'-Tyr-D-Trp-Ala-Trp-D-Phe-Ser-Q X'-Tyr-D-Trp-Ala-Trp-D-Phe-Lys-Q X'-Tyr-D-Trp-Ala-Trp-D-Phe-Glu-Q The peptides of the instant invention can be prepared by classical methods known in the art or, preferably, by using standard solid-phase techniques. The synthesis, for example, can be commenced from the C-terminal end of the peptide using an a-amino protected amino acid. A suitable starting material can be prepared, for instance, by attaching the required a-amino acid to a chloromethylated resin, a hydroxymethyl resin, or a benzhydrylamine resin. One such chloromethylated resin is sold under the tradename BlO-BEADS SX-l by Bio Rad Laboratories, Richmond, California and the preparation of the hydroxymethyl resin is described by Bodanszky et al., Chem. Ind. (London) 38, 1597 (1966). The benzhydrylamine (ALIA) resin has been described by Pietta and Marshall, Chem. Commn. 650 (1970) and is commercially available from Beckman Instruments, Inc., Palo Alto, California in the hydrochloride form thereof (BHA HCl). In the preparation of the compounds of this invention, an a-amino protected amino acid can be coupled to the chloromethylated resin with the aid of, for example, cesium bicarbonate catalyst, according to the method described by Gisin, Relv. Chim. Acta, 56, 1467 (1973). After the initial coupling, the a-amino protecting group can be removed by a choice of reagents including trifluoroacetic acid (TFA) or hydrochloric acid (HCl) solutions in organic solvents at room temperature. After removal of the a-amino protecting group, the remaining protected amino acids can be coupled stepwise in the desired order. Each protected amino acid can be generally reacted in about a 3-fold excess using an appropriate carboxyl group activator such as dicyclohexylcarbodiimide (DCC) in solution, for example, in methylene chloride(CH2Cl2)-dimethyl- formamide (DMF) mixtures. After the desired amino acid sequence has been completed, the desired peptide can be decoupled from the resin support by treatment with a reagent such as hydrogen fluoride (HF) which not only cleaves the peptide from the resin, but also cleaves all remaining side-chain protecting- groups. When the chloromethylated resin is used, hydrogen fluoride treatment results in the formation of the free peptide acids of Formula I (Y = -COOH). When the benzhydrylamine resin is used, hydrogen fluoride treatment results directly in the free peptide amides of Formula I (Y = -CONH2). Alternatively, when the chloromethylated or hydroxymethylated resin is employed, the side-chain protected peptide can be decoupled by treatment of the peptideresin with ammonia to give the desired side-chain protected amide or with an alkylamine to give a sidechain protected alkylamide or dialkylamide. Side-chain protection can then be removed in the usual fashion by treatment with hydrogen fluoride to give the free amides, alkylamides, or dialkylamides. In preparing the esters of this invention, the resins used to prepare the acids of Formula I (Y = -COOH) can be employed and the side-chain protected peptide can be cleaved with base and the appropriate alcohol, i.e., methanol. Side-chain protecting groups can then be removed in the usual fashion by treatment with hydrogen fluoride to obtain the desired ester. The solid-phase procedure discussed above is well known in the art and has been essentially described by J. M. Stewart, Solid Phase Peptide Synthesis: (Freeman and Co., San Francisco, 1969). The growth hormone releasing pentapeptides of Formula I are useful in vitro as unique tools for understanding how growth hormone secretion is regulated at the pituitary level. This includes use in the evaluation of many factors thought or known to influence growth hormone secretion such as age, sex, nutritional factors, glucose, amino acids, fatty acids, as well as fasting and non-fasting states. In addition, the peptides of this invention can be used in the evaluation of how other hormones modify growth hormone releasing activity. For example, it has already been established that somatostatin inhibits growth hormone release. Other hormones that are important and in need of study as to their effect on growth hormone release include the gonadal hormones testosterone, estradiol, and progesterone; the adrenal hormones cortisol and other corticoids, epinephrin and norepinephrine; the pancreatic and gastrointestine hormones, insulin, glucagon, gastric, secretion, the vasoactive intestinal peptides, i.e., bombesin; and the thyroid hormones thyroxine and triiodothyronine. The peptides of the instant invention can also be employed to investigate the possible negative or positive feedback effects of some of the pituitary hormones, e.g., growth hormone and endorphin peptides, on the pituitary to modify growth hormone release. Of particular scientific importance is the use of these peptides to elucidate the subcellular mechanisms mediating the release of growth hormone. The peptides of the present invention can also be administered to warm blooded animals, including man, to release growth hormone in vivo. For example, the peptides can be administered to treat symptoms related to growth hormone deficiencies. In addition, these peptides can be administered to commercially important animals to accelerate and increase their rate and extent of growth. Accordingly, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the peptides within the scope of this invention in association with a pharmaceutical carrier or diluent. The compounds of this invention can be administered by oral, parenteral (intramuscular, intraperitoneal, intravenous (IV) or subcutaneous injection), nasal, vaginal, rectal or sublingual routes of administration and can be' formulate'd in dosage forms appropriate for each route of administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides, such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents. Preparations according to this invention for parental administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteriaretaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax. Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art. The dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient shall be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. Generally, dosage levels of between 0.001 to 10 mg/kg. of body weight daily are administered to mammals to obtain effective release of growth hormone. The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention. Example 1 Synthesis of H2N-Tyr-D-Trp-Ala-Trp-D-Phe-Gln-CONH2 BHA-HCl resin was placed in a reaction vessel. The following procedure was then employed in conjunction with a Beckman brand Peptide Synthesizer Model No. 990 in preparing the hexapeptide H2N-Tyr-D Trp-Ala-Trp-D-Phe-Gln-CONH2: 1. Methylene chloride (CH2Cl2; about 10 mi/gm of BHA.HCl resin) was added to the reaction vessel. The BHA.HCl resin was washed with vigorous stirring for about 1.5 minutes. The CH2C12 solution was then drained from the reaction vessel. This washing step was repeated once. 2. A triethylamine solution ((Et3N)/CH2C12 (10;90); about 10 ml/gm BHA HCl resin) was added to the washed BHAHCl resin in the reaction vessel. The resulting mixture was vigorously stirred for about 1.5 minutes. The solution was then drained from the reaction vessel. 3. Another Et3N3/CH2C12 (10:90) solution (about 10 ml/gm BHA.HCl) was added to the reaction vessel. The BHA-HCl resin was neutralized by vigorous stirring for about 20 minutes. The solution was then drained from the reaction vessel. 4. CH2C12 (about 10 ml/gm of BHA.HCl resin) was added to the reaction vessel. The resulting mixture was vigorously stirred for about 1.5 minutes. The solution was then drained from the reaction vessel. This procedure was repeated an additional two times. 5. Tertiarybutyloxycarbonyl-glutamine (Boc-Gln; about 2.5 times the theoretical amount of the total binding capacity of the BHA HCl resin originally placed in the reaction vessel) in about 50 ml of dimethylformamide-methylene chloride solution (DMF-CH2Cl2 (1:9)) was added to the reaction vessel. The resulting mixture was vigorously stirred for about 1.5 minutes. 6. A 0.5 molar (M) dicyclohexylcarbodiimide (DCC) in CH2Cl2 solution (about 2.5 times the theoretical amount of total bindi8ng capacity of the BHA.HCl resin originally placed in the reaction vessel) was added td the reaction vessel. The resulting mixture was vigorously stirred until a negative ninhydrin test was obtained (about 120 minutes). The solution was then drained from the reaction vessel. 7. CH2C12 (about 10 ml/gm of BHA-HC1 resin) was added to the reaction vessel. -The resulting solution was vigorously stirred for about 1.5 minutes. The solution was then drained from the reaction vessel. This washing procedure was repeated once. 8. DMF (about 10 ml/gm of BHA HCl resin) was added-to the reaction vessel. The resulting mixure was stirred for about 1.5 minutes. The solution was then drained from the reaction vessel. 9. CH2Cl2 (about 10 ml/gm of BHA HCl resin) was added to the reaction vessel. The resulting mixture was vigorously stirred for about 1.5 minutes. The solution was then drained from the reaction vessel. This washing procedure was repeated an additional two times. 10. A trifluoroacetic acid/methylene chloride solution (TFA/CH2C12 (40:60); about 10 ml/gm of BHA^HCl resin) was added to the reaction vessel. The resulting mixture was vigorously stirred for about 1.5 minutes. The solution was then drained from the reaction vessel. 11. Another TFA/CH2Cl2 (40:60) solution (about 10 ml/gm of BHA HCl resin) was added to the reaction vessel. The resulting mixture was vigorously stirred for about 20 minutes. The solution was then drained from the reaction vessel. 12. CH2C12 (about 10 ml/gm of BHA HCl resin) was added to the reaction vessel. The resultig solution was vigorously stirred for about 1.5 minutes. The solution was then drained from the reaction vessel. This washing procedure was repeated once. 13. A triethylamine solution ((Et3N)/CH2C12 (10:90); about 10 ml/gm BHAHC1 resin) was added to the washed BHA HCl resin in the reaction vessel. The resulting mixture was vigorously stirred for about 1.5 minutes. The solution was then drained from the reaction vessel. 14. Another Et2N3/cH2C12 (10:90) solution (about 10 ml/gm BHA-HCl) was added to the reaction vessel. The BHA-HCl resin ways neutralized by vigorous stirring for about 20 minutes. The solution was then drained from the reaction vessel. 15. Chloroform (CHC13; about 10 ml/gm of BHA-HCl resin) was added to the reaction vessel. The resulting mixture was vigorously stirred for about 1.5 minutes. The solution was then drained from the reaction vessel. 16. An ethanol/methylene chloride solution (EtOH/CH2Cl2 (30:70); about 10 ml/gm of BHA-HCl resin) was added to the reaction vessel. The resulting mixture was yigorously stirred for about 1.5 minutes. The solution was then drained from the reaction vessel. This washing step was repeated once. Steps 4 through 16 were then repeated employing the following sequence of amino acids: Boc-D-Phe Boc-Trp Boc-Ala Boc-D-Trp Boc-Tyr (BrZ*) iBrZ denotes p-bromobenzyloxycarbonyl After completion of the synthesis of the desired peptide resin, the reaction vessel containing the peptide resin was then placed in a dessicator and dried overnight under a vacuum. The dried peptide resin was removed from the reaction vessel and placed in another vessel suitable for HF cleavage. This latter vessel also contained a -magnetic stirring bar. A quantity of anisole sufficient to wet the peptide resin was added to this vessel. The vessel was next connected to an HF line and placed under a vacuum to remove any air therein. The vessel was then cooled to about -78 C. with a dry ice-acetone bath. Doubly distilled HF (about 10 ml/gm of peptide resin) was added to the vessel. The dry ice-acetone bath was then removed from the vessel and replaced by an ice-water bath. The vessel's contents were vigorously stirred for about 45 minutes while the vessel remained immersed in the ice-water bath. Most of the HF in the vessel was then removed by water aspiration. After the majority of HF was removed by water aspiration, the remaining HF and anisole were removed via a vacuum pump. The vessel's contents were washed with about 100 ml of ether to further remove any residual anisole. The peptide was removed from the resin by extraction with 30% aqueous acetic acid (aq.HOAc). The aq-HOAc was lypholized off to yield a fluffy peptide powder. The peptide was then purified by partition chromatography or counter current distribution (CCD) employing a butanol: HOAc: water (4:1:5) system. When further purification was necessary, a Pharmacia LH-20 brand chromatography column was also employed. Example 2 Synthesis of H2N-Tyr-D-Trp-Ala-Trp-D-Phe-Thr-CONH2 The procedure set forth in Example 1 was employed to synthesize the hexapeptide H2N-Tyr-D-Trp Ala-Trp-D-Phe-Thr-CONH2 employing the following sequence of amio acids: Boc-Thr Boc-D-Phe Boc-Trp Boc-Ala Boc-D-Trp Boc-Tyr(BrZ) Example 3 Synthesis of H2N-Tyr-D-Trp-Ala-Trp-D-Phe-Gln-COOH The procedure set forth in Example 1 was employed with several modifications to synthesize the hexapeptide H2N-Tyr-D-Trp-Ala-Trp-D-Phe-Gln-COOH employing the following sequence of amino acids: Boc-Gln Boc-D-Phe Boc-Trp Boc-Ala Boc-D-Trp Boc-Tyr(BrZ) The modifications consisted of: (1) Employing a hydroxymethyl resin in place of BHA-HCl resin. (2) Omitting steps 2-4 of Example 1 and replacing them with a single step which entailed adding N,Ndimethylaminopyridine (about 2.5 times the theoretical amount of total binding capacity of the hydroxymethyl resin originally placed in the reaction vessel) to the reaction vessel. The resulting mixture was vigorously stirred for about 1.5 minutes. The solution was then drained from the reaction vessel. (3) All calculations, where applicable, were based on the amount of hydroxymethyl resin (instead of BHA-HCl resin) originally placed in the reaction vessel. Example 4 Synthesis of H2N-Tyr-D-Trp-Ala-Trp-D-Phe-CONH2 The procedure set forth in Example 1 was employed with several modifications to synthesize the pentapeptide H2N-Tyr-D-Trp-Ala-Trp-D-Phe-CONH2 employ -ing the following sequence of amino acids: Boc-D-Phe Boc-Trp Boc-Ala Boc-D-Trp Boc-Tyr-BrZ) The modifications consisted of: (1) Substituting the following steps for steps 5 and 6 of Example 1: 5. An 0.5 molar (M) dicyclohexylcarbodiimide (DCC) in CH2Cl2 solution (about 2.5 times the theoretical amount of total binding capacity of the BRA-HCl resin originally placed in the reaetion vessel) was added to the reaction vessel. The resulting mixture was vigorously stirred for about 1.5 minutes. The solution was then drained from the reaction vessel. 6. Tertiarybutyloxycarbonyl-D-phenylalanine (Boc-D-Phe; about 2.5 times the theoretical amount of the total binding capacity of the BHA HC1 resin originally placed in the reaction vessel) in about 50 ml of DME-CH2C12 (5:45) solution was added to the reactin vessel. The resulting mixture was vigorously stirred until a negative ninhydrin test was obtained (about 120 minutes). The solution was then drained from the reaction vessel. (2) Omitting steps 12-14 of Example 1. (3) After employing steps 1-16 of Example 1, as modified herein by (1) and (2) of this Example 4, with respect to the first amino acid, Boc-D-Phe, these modified steps 1-16 were then repeated for the remaining amino acids of the above sequence. 4. The peptide was purified by partition chromatography employing a butanol: HOAc: water (4:1:5) system. Example 5 Synthesis of H2N-Tyr-D-Trp-Asn-Trp-D-Phe-CONH? The procedure set forth in Example 4 was employed with one modification to synthesize the penta peptide H2N-Tyr-D-Trp-A±n-Trp-D-Phe-CO12 employing the following sequence of amino acids: Boc-D-Phe Bcc-Trp Boc-Asn ONP* Boc-D-Trp Boc-Tyr(BrZ) *ONP denotes para-nitrophenylester. The sole modification entailed in the omission of step 5 prior to the addition of Boc-Asn-ONP to the intermediate peptide resin. Example 6 Synthesis of H2N-Tyr-D-Trp-Ala-Trp-D-Phe-COOH The procedure set forth in Example 4 was employed with several modifications to synthesize the pentapeptide H2N-Tyr-D-Trp-Ala-Trp-D-Phe-COOH employing the following sequence of amino acids: Boc-D-Phe Boc-Trp Boc-Ala Boc-D-Trp Boc-Tyr(BrZ) The modifications consisted of: (1) Employing a hydroxymethyl resin in place of BHAHCl resin. (2) Omitting steps 2-4 of Example 4 and replacing them with a single step which entailed adding N,Ndimethylaminopyridine (about 2.5 times the theoretical amount of total binding capacity of the hydroxymethyl resin originally placed in the reaction vessel) to the reaction vessel. The resulting mixture was vigorously stirred for about 1.5 minutes. The solution was then drained from the reaction vessel. (3) All calculations, where applicable, were based on the amount of hydroxymethyl resin (instead of BHA z HCl resin) originally placed in the reaction vessel. Example 7 Synthesis of H2N-Tyr-D-Trp-Ser-Trp-D-Phe-CONH2 The procedure set forth in Example 4 was employed to synthesize the pentapeptide H2N-Tyr-D-Trp Ser-Trp-D-Phe-CONH2 employing the following sequence of amino acids: Boc-D-Phe Boc-Trp Boc-Ser(Bz)* Boc-D-Trp Boc-Tyr(BrZ) *Bz denotes benzyl Example 8 Synthesis of H2N-Trp-D-Phe-Ala-Tyr-D-Leu-CONH2 The procedure set forth in Example 4 was employed to synthesize the pentapeptide H2N-Trp-D-Phe Ala-Tyr-D-Leu-CONH2 employing the following sequence of amino acids: : Boc-D-Leu Boc-Tyr(BrZ) Boc-Ala Boc-D-Phe Boc-Trp Example 9 Synthesis of H2N-Trp-D-Phe-Al a-Tyr-Met-CONH2 The procedure set forth in Example 4 was employed to synthesize the pentapeptide H2N-Trp-D-Phe Al a-Tyr-Met-CONH2 employing the following sequence of amino acids: Boc-Met Boc-Tyr (BrZ) Boc-Ala Boc-D-Phe Boc-Trp Example 10 Synthesis of H2N-D-Trp-D-Phe-D-Phe-Lys-Met-CONH2 The procedure set forth in Example 4 was employed to synthesize the pentapeptide H2N-D-Trp-D Phe-D-Phe-Lys-Met-CONH2 employing the following se quence of amino acids: Boc-Met Boc-Lys(Z)* Boc-D-Phe Boc-D-Phe Boc-D-Trp *Z denotes benzyloxycarbonyl; see Example 12, infra, for preparation of Boc-Lys(Z). Example 11 synthesis of H2N-Trp-D-Phe-D-Phe-Lys-Met-CONH2 The procedure set forth in Example 4 was employed to synthesize the pentapeptide H2N-Trp-D-Phe D-Phe-Lys-Met-CONH2 employing the following sequence of amino acids: Boc-Met Boc-Lys(Z) Boc-D-Phe Boc-D-Phe Boc-Trp Example 12 Preparation of Boc-Lys(Z) Into a separatory funnel was placed the dicyclohexyl ammonium salt (DCHA) of Boc-Lys(Z)(Boc Lys(Z)DCHA; about 3 times the theoretical amount of the total binding capacity of the BHA-HC1 resin originally placed in the reaction vessel in Example 1). About 40 ml of ethyl acetate (EtOAc) was next added to the separatory funnel. Sulfuric acid (H2SO4; 1N) in an amount sufficient to acidify the solid Boc-Lys(Z) DCHA) was then added to the separatory funnel. The separatory funnel and its contents were shaken vigorously and afterwards the EtOAc and H2O layers were alloed to separate. The H2O layer was drained from the separatory funnel. H2O was added to the separatory funnel and the shaking, standing, draining cycle was repeated. A sufficient amount of sodium sulfate (Na2SO4) to absorb any residual H2O remaining in the EtOAc was added to the -EtOAc solution of Boc-Lys(Z). The resulting mixture was then filtered to remove the Na2 504 therefrom. The filtered solution was then employed in the synthesis procedure set forth in Example 10, supra. An analogous procedure was also employed to prepare the Boc-Lys(Z) used in Example 11, supra, and Examples 14 and 16, infra. Example 13 Synthesis of H2N-D-Trp-D-Trp-Phe-CONH2 The procedure set forth in Example 4 was employed to synthesize the tripeptide H2N-D-Trp-D-Trp Phe-CONli2 employing the following sequence of amino acids: Boc-Phe Boc-D-Trp Boc-D-Trp Example 14 Synthesis of H2N-D-Lys-Tyr-D-Trp-D-Trp-Phe-CONH2 The procedure set forth in Example 4 was employed to synthesize the pentapeptide H2N-D-Lys-Tyr D-Trp-D-Trp-Phe-CONH2 employing the following sequence of amino acids: Boc-Phe Boc-D-Trp Boc-D-Trp Boc-Tyr(BrZ) Boc-D-Lys(Z) Example 15 Synthesis of H2N-Tyr-Gly-D-Trp-Phe-D-Phe-CONH2 The procedure set forth in Example 4 was employed to synthesize the pentapeptide H2N-Tyr-Gly D-Trp-Phe-D-Phe-CONH2 employing the following sequence of amino acids: : Boc-D-Phe Boc-Phe Boc-D-Trp Boc-Gly Boc-Tyr(BrZ) Example 16 Synthesis of H2N-D-Phe-Trp-D-Phe-Phe-Lys-CONH2 The procedure set forth in Example 4 was employed to synthesize the pentapeptide H2N-D-Phe-Trp D-Phe-Phe-Lys-CONH2 employing the following sequence of amino acids: Boc-Lys(Z) Boc-Phe Boc-D-Phe Boc-Trp Boc-D-Phe Example 17 Synthesis of H2N-D-Phe-Trp-D-Phe-Phe-Met-CONH2 The procedure set forth in Example 4 was employed to snthesize the pentapeptide H2N-D-Phe-Trp D-Phe-Phe-Met-CONE2 employing the following sequence of amino acids: : Boc-Met Boc-Phe Boc-D-Phe Boc-Trp Boc-D-Phe Example 18 Synthesis of H2N-D-Phe-Phe-D-Trp-Phe-Met-CONH2 The procedure set forth in Example 4 was employed to synthesize the pentapeptide H2N-D-Phe-Phe D-Trp-Phe-Met-CONH2 employing the following sequence of amino acids: Boc-Met Boc-Phe Boc-D-Trp Boc-Phe Boc-D-Phe Example 19 Synthesis of H2N-Tyrp-D-Trp-D-Trp-Phe-CONH2 The procedure set forth in Example 4 was employed to synthesize the tetrapeptide H2N-Tyr-D-Trp D-Trp-Phe-CONH2 employing the following sequence of amino acids: Boc-Phe Boc-D-Trp Boc-D-Trp Boc-Tyr(BrZ) Example 20 Synthesis of H2N-Tyr-D-Trp-D-Trp-Tyr-CONH2 The procedure set forth in Example 4 was employed to synthesize the tetrapeptide H2N-Tyr-D-Trp D-Trp-Tyr-CONH2 employing the following sequence of amino acids: : Boc-Tyr(BrZ) Boc-D-Trp Boc-D-Trp Boc-Tyr(BrZ) Example 21 Synthesis of H2N-Tyr-D-Trp-D-Trp-Phe-Met-CONH2 The procedure set forth in Example 4 was employed to synthesize the pentapeptide H2N-Tyr-D-Trp D-Trp-Phe-Met-CONH2 employing the following sequence of amino acids: Boc-Met Boc-Phe Boc -D-Trp Boc-D-Trp Boc-Tyr(BrZ) Example 22 In Vitro Growth Hormone Release Study Female rats of the CD-1 strain were housed in a constant temperature room at 240C. with 14 hours light and 10 hours darkness. The rats were fed Purina brand rat chow ab libitum. All studies were started between 0800 and 1000 hours. Pituitaries were removed from 20 day old female rats. In each of fifteen polytetrafluoroethylene beakers (10 ml) were incubated two pituitaries at 360C. in 1 ml of lactated Ringer's solution in a Dubnoff Shaker (90 cycles/min.). Three beakers were employed for each of the dosage levels shown in Table II. All medium in each beaker was removed each hour (e.g., P1, P2, I3, 14) and then fresh medium was added back to each beaker. Each medium removed was assayed for GH, in duplicate, by a standard radioimmunoassay (RIA). The growth hormone radioimmunoassay reagents were distributed by The National Institute of Arthritis and Metabolic Disease Division (NIAMDD) program. The GH values were recorded in terms of nanograms (ng) of a rat standard with a growth hormone potency of 0.61 units/mg. The growth hormone agonist of Example 1 was not added to the incubation mediums employed during the first hour of the incubation period (P1) or to the incubation mediums employed during the second hour of the incubation period (P2). The growth hormone agonist of Example 1 was dissolved in dimethylsulfoxide (DMSO; 10;1, agonist:DMSO), added to each incubation medium employed during the third hour of the incubation period (I3) and to each medium employed during the fourth hour of the incubation period (I4). The release of growth hormone was recorded as AGH and calculated by subtracting the amount of Cli released at P2 from that released at I3 and 14. The agonist activity was determined from the release at I3 and 14. The mean of the 6 AGH values obtained from each of the three beakers per dosage level measured at I3 and 14 are set forth in Table II. Example 23 In Vitro Growth Hormone Release Study The procedure set forth in Example 22 was employed in an in vitro growth hormone release study of the peptides of Examples 2-11 and 13-21 and the results therefrom are also set forth in Table II. TABLE II IN VITRO GROWTH HORMONE RELEASE1,2 Dosage3 : 3 Control - 0.3 g Peptide Control 0.01 g 0.1 g 0.3 g HN2-Tyr-D-Trp-Ala-Trp-D-Phe-Gln-CONH -40#35 240#965 2000#5236 N/A4 H2N-Tyr-D-Trp-Ala-Trp-D-Phe-Thr-CONHê -40#35 94#6935 650#3205 N/A H2N-Tyr-D-Trp-Ala-Trp-D-Phe-Gln-COONê -40#35 N/A 753#5395 N/A H2N-Tyr-D-Trp-Ala-Trp-D-Phe-CONH -345#105 N/A 3409#455 4540#1200 H2N-Tyr-D-trp-Ser-Trp-D-Phe-CONHê -140#185 N/A 353#1445 N/A H2N-Trp-D-Phe-Ala-Tyr-D-Leu-CONH2 -96#68 N/A N/A N/A H2N-Trp-D-Phe-Ala-Tyr-Met-CONH2 -99#109 N/A N/A N/A 1. #GH given in terms of ng/ml incubation medium # standard error of the mean (SEM) 2. P Value < 0.001 unless otherwise noted. P value is a comparison of the GH levels in medium containing growth hormone agonist analog to the GH levels in medium (control) without the agonist. Accordingly, the control does not have a P Value. 3. Dosage given in terms of g/ml incubation medium. 4. N/A denotes not available. 5. P Value not significant. 6. P Value < 0.01. 7. P Value #0.01 8. P Value < 0.05. 9. P Value #0.02 10. P Value < 0.02. TABLE II (Continued) Dosage: 1 -100 g Peptide 1 g 10 g 20 g 100 g H2N-Tyr-D-Trp-Ala-Trp-D-Phe-Gln-CONH2 4235#785 4141#576 N/A N/A 6 6 H2N-Tyr-D-Trp-Ala-Trp-D-Phe-Thr-CONH2 2167#591 2957#834 N/A N/A 6 H2N-Tyr-D-Trp-Ala-Trp-D-Phe-Gln-COOH 2759#515 3994#1214 N/A N/A H2N-Tyr-D-Trp-Ala-Trp-D-Phe-CONH2 4611#510 5000#662 N/A N/A H2N-Tyr-D-Trp-Ser-Trp-D-Phe-CONH2 3119#413 3831#365 N/A N/A 6 7 7 H2N-Trp-D-Phe-Ala-Tyr-D-Leu-CONH2 238#67 1224#305 N/A 1470#487 6 H2N-Trp-D-Phe-Ala-Tyr-Met-CONH2 N/A 1001#207 N/A 882#283 5 H2N-D-Trp-D-Phe-D-Phe-Lys-Met-CONH2 147#88 853#138 N/A 2024#254 5 8 H2N-Trp-D-Phe-D-Phe-Lys-Met-CONH2 - 108#52 440#180 N/A 861#160 6 H2N-D-Trp-D-Trp-Phe-CONH2 943#137 1263#293 N/A 635#165 6 H2N-D-Lys-Tyr-D-Trp-D-Trp-Phe-CONH2 1046#266 N/A 1487#197 1654#329 H2N-Tyr-Gly-D-Trp-Phe-D-Phe-CONH2 200#167 1384#120 N/A 1196#194 5 9 H2N-D-Phe-Trp-D-Phe-Phe-Lys-CONH2 - 109#101 888#120 N/A 963#96 H2N-D-Phe-Trp-D-Phe-Phe-Met-CONH2 N/A 1469#153 N/A 1483#168 5 6 5 H2N-D-Phe-Phe-D-Trp-Phe-Met-CONH2 130#143 955#248 N/A 1060#469 H2N-Tyr-D-Trp-D-Trp-Phe-CONH2 686#82 1790#-60 N/A 984#355 5 H2N-Tyr-D-Trp-D-Trp-Tyr-CONH2 1111#572 1898#267 N/A N/A 9 H2N-Tyr-D-Trp-D-Trp-Phe-Met-CONH2 1697#222 N/A 1530#208 219#113 TABLE II (Continued) Dosage3 : Control - 0.3 g Peptide Control 0.01 g 0.1 g 0.3 g N2N-D-Trp-D-Phe-D-Phe-Lys-Met-CONH2 58#48 N/A N/A N/A H2N-Trp-D-Phe-D-Phe-Lys-Met-CONH2 -79#55 N/A N/A 24#245 H2N-D-Trp-D-Trp-Phe-CONH2 180#108 N/A N/A 592#2379 H2N-D-Lys-Tyr-D-Trp-D-Trp-Phe-CONH2 - 180#108 N/A N/A N/A H2N-Tyr-Gly-D-Trp-Phe-D-Phe-CONH2 - 198#85 N/A N/A N/A H2N-D-Phe-Trp-D-Phe-Phe-Lys-CONH2 237#264 N/A N/A N/A H2N-D-Phe-Trp-D-Phe-Phe-Met-CONH2 146#172 N/A N/A N/A H2N-D-Phe-Phe-D-Trp-Phe-Met-CONH2 46#61 N/A N/A N/A H2N-Tyr-D-Trp-D-Trp-Phe-CONH2 - 31#58 N/A 453#48 N/A H2N-Tyr-D-Trp-D-Trp-Tyr-CONH2 - 170#42 N/A N/A 345#1036 H2N-Tyr-D-Trp-D-Trp-Phe-Met-CONH2 - 54#35 N/A N/A N/A The results se-t forth in Table II demonstrate that peptides within the scope of the instant invention can induce a significant in vitro release of growth hormone from the pituitary. By introducing various other hormones, e.g., somatostatin, testosterone, ccrtisol, insulin, etc. into the incubation medium of Examples 22 and 23, one can study what effect these latter hormones have on the regulation of growth hormone secretion. Example 24 In Vivo Diagnostic Application A peptide within the scope of this invention is injected It into a mammal, including a human. Blood samples are taken before and at +15 minute intervals after the IV injection for about 1 to about 2 hours. Serum growth hormone levels are measured on each of the blood samples. The rise in growth hormone level is an index of the response. The degree of the growth hormone response is indicative of whether the hypothalmicpituitary unit is functioning normally to secrete growth hormone. This test can be employed for evaluating whether the hypothalamic-pituitary system is normal under a large number of different clinical and experimental conditions in both healthy and disease states The test has application at all ages and in both sexes. Based on this disclosure, many other modifications and ramifications will naturally suggest themselves to those skilled in the art. These are intended to be comprehended as within the scope of this invention.

Claims: CLAIMS: 1. A peptide having a formula selected from a group consisting of X-Y1-Z1-E1-G1-J1-Q X-Y2-Z2-E2-G2-J2-Q X-Y3-Z3-E3-G3-J3-Q X-Y4-Z4-E4-Q X-Y5-Z5-E5-J5-Q X-Y6-Z6-E6-J6-Q X-Y7-Z7-E7-G7-J7-Q X-Y8-Z8-E8-G8-Q X-Y9-Z9-E9-G9-J9-Q X'-Y10-Z10-E10-G10-J10-L10-Q and their pharmaceutically acceptable non-toxic acid addition salts, wherein X is selected from a group consisting of -NH2, -NHCH3, and -N(CH3)2; Y1, G1, Y2, G2, E4, Z5, J5, Y6, G6, Z7, G7, 68, G8, Y9, G9, Y10, and G10 are selected from a group consisting of Tyr, Trp, and Phe; Z1, J1, Z2, Z3, E3, Y4, Z4, E5, G5, E6, J6, Y7, E7, Z8, E8, Z9, E9, Z10, and J10 are selected from a group consisting of D-Tyr, D-Trp, and D-Phe; J3 and Z6 are selected from a group consisting of Gly, Ala, Val, Leu, Ile, Pro, Hyro, Ser, Thr, Cys, and Met; ; E1 is selected from a group consisting of Gly, Ala, Val, Leu, Ile, Pro, HyPro, Ser, Thr, Cys, Met, Asp, Gln, and His; E2 is selected from a group consisting of Gly, Ala, Val, Leu, Next, and Ile; J2 is selected from a group consisting of Gly, Ala, D-Ala, Val, D-Val, Leu, D-Leu, Ile, D-Ile, Pro, D-Pro, Hypro, D-Hypro, Ser, D-Ser, Thr, D-Thr, Cys, D-Cys, Met, and D-Met; Y3 is selected from a group consisting of Tyr, D-Tyr, Trp, D-Trp, Phe, and D-Phe; G3 is selected from a group consisting of Lys and Arg; Y5 is selected from a group consisting of D-Lys and D-Arg; J7 is selected from a group consisting of Gly, Ala, Val, Leu, Ile, Pro, Hypro, Ser, Thr, Cys, Met, Asp, Glu, Asn, Gln, Arg, and Lys; Jg is selected from a group consisting of natural amino acids and the D-configuration thereof; ; X' is selected from a group consisting of -NHCOCH3, -NH2, -'NHCH3, and -N(CH3)2; E10 is selected from a group consisting of Gly, Ala, Val, Leu, Ile, Ser, Thr, Met, Asp, and Gln; L10 is selected from a group consisting of Asn, Gln, Glu, Arg, Lys, Ser, and Thr; and Q is selected from a group consisting of -CONH2, -CONHR, -CONR1R2,-CH2OR, -CH2OH, -COOH, and -COOR, wherein each R, R1, and R2 is selected from a group consisting of straight and branched alkyl groups containing 1-6 carbon atoms. 2. The peptide of claim 1 having the formula selected from the group consisting of X-Tyr-D-Trp-E1-Trp-D-Phe-Q X-Trp-D-Phe-Ala-Tyr-J2-Q X-Y3-D-Phe-D-Phe-Lys-Met-Q X-D-Trp-Z4-E4-Q X-D-Lys-Tyr-D-Trp-D-Trp-Phe-Q X-Tyr-Gly-D-Trp-Phe-D-Phe-Q X-D-Phe-Z7-E7-Phe-J7-Q X-Y8-D-Trp-E8-G8-Q X-Tyr-D-Trp-D-Trp-Tyr-Q X-Y9-D-Trp-E9-G9 -J9 -p X'-Tyrp-DTrp-E10-Trp-D-Phe-L10-Q wherein E4, Z7, G8, and Gg are selected from the group consisting of Trp and Phe; Z4, E7, E8, and Eg are selected from the group consisting of D-Trp and D-Phe; E1 is selected from the group consisting of Gly, Ala, Val, Leu, Ile, Ser, Thr, Asn, and Gln; J2 is selected from the group consisting of DLeu and Met; ; Y3 is selected from the group consisting of Trp and D-Trp; J7 is selected from a group consisting of Lys and Met; Jg is selected from a group consisting of Met, D-Met, Leu, D-Leu, Phe, D-Phe, Arg, D-Arg, Pro, and D-Pro; E10 is selected from the group consisting of Gly, Ala, Val, Leu, Ile, Ser, Thr, Asn, and Gln; and L10 is selected from the group consisting of Asn, Gln, Arg, Lys, Ser, and Thr. 3. The peptide of claim 2 having the formula X-Tyr-D-Trp-Ala-D-Phe-L10-Q. 4. The peptide of claim 1 having a formula selected from the group consisting of X-Tyr-D-Trp-Ala-D-Phe-Gln-Q; and X-Tyr-D-Trp-Ala-D-Phe-Thr-Q. 5. The peptide. of claim 1 having a formula selected from a group consisting of H2N-Tyr-D-Trp-Ala-Trp-D-Phe-CONH,; H2N-Tyr-D-Trp-Ser-Trp-D-Phe-CONH2; H2N-Tyr-D-Trp-Ala-Trp-D-Phe-COOH; H2N-Trp-D-Phe-Ala-Tyr-D-Leu-CONH2; H2N-Trp-D-Phe-Ala-Tyr-Met-CONH2; H2N-D-Trp-D-Phe-D-Phe-Lys-Met-CONH2; H2N-Trp-D-Phe-D-Phe-Lys-Met-CONH,; H2N-D-Trp-D-Trp-Phe-CONH2; H2N-D-Lys-Tyr-D-Trp-D-Trp-Phe-CONH2; H2N-Tyr-Gly-D-Trp-Phe-D-Phe-CONH2; H2N-D-Phe-Trp-D-Phe-Phe-Lys-CONH2; H2N-D-Phe-Trp-D-Phe-Phe-Met-CONH2; H2N-D-Phe-Phe-D-Trp-Phe-Met-CONH2; H2N- Tyr-D-Trp-D-Trp-Tyr-CONH2; H2N-Tyr-D-Trp-D-Trp-Phe-Met-CONH2; H2N-Tyr-D-Trp-Ala-Trp-D-Phe-Gln-CONH2; H2N-Tyr-D-Trp-Ser-Trp-D-Phe-Thr-COEI ; and H2N-Tyr-D-Trp-Ala-Trp-D-Phe-Gln-COOH. 6. The -peptide of claims 1-3 or 4 wherein each R, Rl, and R2 of Q is selected from the group consisting of alkyl groups containing 1-2 carbon atoms. 7. The peptide of claims 1-3 or 4 wherein Q is -CONH2. 8. A method of releasing growth hormone from a pituitary comprising contacting said pituitary with the peptide of claims 1-6 or 7. 9. A compound of a formula selected from a group consisting of Boc-Tyr(BrZ)-D-Trp-Ala-Trp-D-Phe-#; Boc-Tyr(BrZ)-D-Trp-Ala-Trp-D-Phe-#'; Boc-Tyr(BrZ)-D-Trp-Ser(Bz)-Trp-D-Phe-; Boc-Trp-D-Phe-Ala-Tyr(BrZ )-Met-&commat;; Boc-Trp-D-Phe-Ala-Tyr(BrZ)-D-Leu-&commat;; Boc-D-Trp-D-Phe-D-Phe-Lys(Z)-Met-&commat;; Boc-Trp-D-Phe-D-Phe-Lys(Z)-met-#; Boc-D-Trp-D-Trp-Phe-&commat;; Boc-D-Lys(Z)-Tyr(BrZ)-D-Trp-D-Trp-Phe-#; Boc-Tyr(BrZ)-Gly-D-Trp-Phe-d-Phe-#; Boc-D-Phe-Trp-D-Phe-Phe-Lys(Z)-&commat;; Boc-D-Phe-Trp-D-Phe-Phe-Met-; Boc-D-Phe-Phe-D-Trp-Phe-Met-&commat;; Boc-Tyr(BrZ)-D-Trp-D-Trp-Phe#; Boc-Tyr(BrZ)-D-Trp-D-Trp-Tyr(Z)-&commat;; Boc-Tyr(BrZ)-D-Trp-D-Trp-Phe-Met-&commat;; Boc-Tyr(BrZ)-D-Trp-Ala-Trp-D-Phe-Gln-#; Boc-Tyr(BrZ)-D-Trp-Ala-Trp-D-Phe-Gln-&commat;'; ; and Boc-Tyr(BrZ)-D-Trp-Ala-Trp-D-Phe-Thr-# wherein BrZ is p-bromobenzyloxycarbonyl; Boc is t-butoxycarbonyl; Bz is benzyl; Z is benzyloxycarbonyl; &commat;' is hydroxymethyl resin; and is benzhydrylamine resin.

Inventors: MOMANY, FRANK A.
Applicants: BECKMAN INSTRUMENTS, INC.
Application year: 1980
Main classification: C07C103
IPC codes: C07K5, C07K14, C07K7, A61K38