THERAPEUTIC PEPTIDES

Abstract: A linear peptide which is an analog of naturally occurring, biologically active substance P having an active site and a binding site responsible for the binding of said peptide to a receptor on a target cell. The analog has a non-peptide bond instead of a peptide bond between an amino acid residue of said active site and an adjacent amino acid residue, or a synthetic, a beta -amino acid, or a gamma -amino acid residue replacing two amino acid residues of the active site.

Description: THERAPEUTIC PEPTIDES Background of the Invention This invention relates to therapeutic peptides, in particular analogs of the naturally occurring peptide substance P. Substance P (SP) has numerous pharmacologic effects including vasodilation and hypotension, contraction of non- vascular smooth muscle, stimulation of salivary and pancreatic secretion, depolarization of various neurons and histamine release from mast cells. SP is thought to play a variety of physiological roles (many of which are associated with the induction of pain) . These include regulation of peristalsis and smooth muscle activity in the gastrointestinal tract, regulation of salivary and pancreatic secretion, regulation of the inflammatory response to peripheral tissue injury, neurotransmission, and regulation of neuro- immunomodulation. Mantyh et al. (1989) Proc. Natl. Acad. Sci. USA 86:5193 reports the presence of substance P receptors at wound sites in the central nervous system and suggests that SP may be involved in regulating the response to injury in the central nervous system as well as in peripheral tissues. Substance P is also a proliferative agent, stimulat the proliferation of fibroblasts, T-lymphocytes, e. -helial cells, smooth muscle cells and astrocytes. SP belongs to a family of bioactive peptides known as the tachykinins. The structure, activity, and function of SP and other tachykinins are discussed in Payan (1989) Ann. Rev. Med. 0:341. As discussed in Payan, SP shares common pharmacological properties and a conserved carboxyl terminal sequence (Phe-X-Gly-Leu- et-NH-, where X is a branched aliphatic or aromatic amino acid residue) with the other tachykinins. The principle biological activities, and the ability to bind to a receptor, reside in the carboxy1 terminal sequence of these peptides. Selectivity toward a specific tachykinin receptor is determined by the amino-terminal sequence of the peptides Iverson et al., (1989) The Tachykinin System, Abstract presented at the llth American Peptide Symposium. The conservation of carboxyl terminal sequence extends beyond SP and other mammalian tachykinins to other bioactive peptides, as shown in Table l. Numerous derivatives of SP, made by side chain modification and/or D-amino acid substitution, have been shown to act as SP receptor antagonists. Folkers, U.S. Patent No. 4,481,139, describes substance P antagonists made by D or L amino acid substitution. These antagonists include the undecapeptide analog spantide (D-Arg-Pro-Lys-Pro-Gln-Gln-D-Trp- Phe-D-Trp-Leu-Leu- NH 2 ) as well as truncated analogs of substance P. Jensen et al. (1988) Am. J. of Physiol. 254: G883 characterized the ability of various SP antagonists to inhibit the action of bombesin. Jensen et al. studied four SP analogues: Arg-D-Pro- Lys-Pro-Gln-Gln-D-Phe-Phe-D-Trp-Leu-Met-NH,; Arg-D-Pro-Lys-Pro- Gln-Gln-D-Trp-Phe-D-Trp-Leu-Met-NH_; D-Arg-D-Pro-Lys-Pro-Gln-Gln-D-Trp-Phe-D-Trp-Leu-Leu-NH.; and D- Arg-Pro-Lys-Pro-Gln-Gln-D-Trp-Phe-D-Trp-Leu-Leu-NH-. Jensen et al. also studied two SP analogues with the first 3 amino acid residues deleted, D-Pro-Gln-Gln-D-Trp-Phe-D-Trp-Leu-Met-NH 2 and D-Pro-Gln-Gln-D-Trp-Phe-D-Trp-D-Trp- et-NH None of these receptor binding peptides are, however, specific to the SP receptor. All were found to inhibit bombesin-stimulated amylase release. Jensen et al. concluded that "the ability to inhibit the action of bombesin is a general property of SP analogues that also function as SP receptor antagonists and that the SP receptor antagonists are each inhibiting the action of bombesin by functioning as bombesin receptor antagonists." Woll et al. (1988) Proc. Nat. Acad. Sci. USA 85: 1857 found the substance P antagonist D-Arg-Pro-Lys-Pro-D-Phe-Gln- D-Trp- Phe-D-Trp-Leu-Leu-NH 2 a potent bombesin antagonist in murine Swiss 3T3 cells. Agonists and antagonists of a wide spectrum of biologically active peptide hormones, including substance P, have been synthesized by the introduction of modification of the peptide bonds of the peptide hormone, see Spatola (1983) in Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins (B. einstein, ed.) M. Dekker, New York and Basel, pp. 267-357, for a recent review of the field. Abbreviations (uncommon) : cyclohexyl-Ala = (cyclohexyl alanine) Lys-e-NHR = lysine wherein the e-N atom carries an R group (where R is any of H, C 1 _ 12 alkyl, - phenylalkyl, COE (where E is C 1 _ 20 alkyl, C 3 _ 2Q alkenyl, C 3 _ 2Q alkinyl, phenyl, naphthyl, or C 7 _ 1Q phenylalkyl) , or C^ ^ -C acyl) ; Nle - H 2 N-CH-C00H (norleucine) (CH 2 ) 3 -CH 3 identifying group Nal = naphthylalanine pGlu= (pyroglutamic acid) Sar = sarcosine Sta (statine) = (3S, 4S)-4-amino-3-hydroxy-6-methylheptanoic acid, and has the chemical structure: group AHPPA = (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoic acid, and has the chemical structure: ACHPA = (3S, 4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid and has the chemical structure: group SP = Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH 2 (substance P) . Summary of the Invention In general, the invention features a linear (i.e., non- cyclic) peptide which is an analog of naturally occurring, biologically active substance P having an active site and a binding site responsible for the binding of the peptide to a receptor on a target cell. The analog has one of the following modifications: (a) a non-peptide bond instead of a peptide bond between an amino acid residue of the active site and an adjacent amino acid residue, (b) a replacement of two amino acid residues within the active site with a synthetic amino acid residue, e.g., statine, AHPPA, ACHPA, a β-amino acid residue, or a γ-amino acid residue, (c) a deletion of an amino acid residue within the active site and a modification of an amino acid residue outside of the active site, or (d) the presence of an N-terminal amino acid residue that is not the naturally occurring amino acid residue of said naturally occurring, biologically active peptide (where β- or γ- is not designated an amino acid is an α-amino acid) . In preferred embodiments the analog is capable of acting as a competitive inhibitor of naturally occurring substance P by binding to the receptor and, by virtue of one of the modifications, failing to exhibit the in vivo biological activity of the naturally occurring peptide. In preferred embodiments the active site of the linear peptide is in the carboxyl terminal-half of the linear peptide. The linear peptide has one of the following modifications: (a) a non-peptide bond instead of a peptide bond between an amino acid residue of the active site and an adjacent amino acid residue, (b) a replacement of two am."no acid residues within the active site with a synthetic aminc icid residue, e.g., statine, AHPPA, ACHPA, a β-amino acid residue, or a γ-amino acid residue, (c) a deletion of an amino acid residue within the active site and a modification of an amino acid residue outside of the active site, or (d) the presence of an N-terminal amino acid residue that is not the naturally occurring amino acid residue of said naturally occurring, biologically active peptide. In preferred embodiments the active site of the linear peptide is in the carboxyl terminal-half of the linear peptide. The linear peptide has one of the following modifications, (a) a non-peptide bond instead of a peptide bond between the carboxyl terminal amino acid residue and the adjacent amino acid residue, or (b) a statine or AHPPA or ACHPA, β-amino acid, or γ-amino acid residue in place of the naturally occurring carboxyl terminal and adjacent amino acid residues. In preferred embodiments the analog of substance P has one of the following modifications, (a) a non-peptide bond instead of a peptide bond between the carboxyl terminal amino acid residue and the adjacent amino acid residue, or (b) a statine or AHPPA or ACHPA, β-amino acid, or γ-amino acid residue in place of the naturally occurring carboxyl terminal and adjacent amino acid residues. In preferred embodiments the linear peptide is an analog of substance P with an active site in the carboxyl terminal-half of the linear peptide. The analog of substance P has one of the following modifications: (a) a non-peptide bond instead of a peptide bond between the carboxyl terminal amino acid residue and the adjacent amino acid residue, or (b) a statine or AHPPA or ACHPA or β-amino acid or γ-amino acid residue in place of the naturally occurring carboxyl terminal and adjacent amino acid residues. The linear peptides for which introduction of a non-peptide bond between two amino acid residues, or the replacement of two natural amino acid residues with a synthetic amino acid residue, a β-amino acid residue, or a γ-amino acid residue, or the deletion ("des") of the C-terminal amino acid residue useful in creating or enhancing antagonist activity are those in which activity is associated with the two C-terminal amino acid residues of the amino acid chain. Therefore, the active site of the naturally occurring peptide of which the peptides of the invention are analogs preferably includes at least on amino acid residue in the carboxy terminal half of the peptide, and the linear peptide of the invention includes that amino acid residue in its carboxy terminal half. Modifications can be introduced in a region involved in receptor binding, or in a non-binding region. By non-peptide bond is meant that the carbon atom participating in the bond between two residues is reduced from a carbonyl carbon to a methylene carbon, i.e., CH -NH; or, less preferably, CH 2 -S, CH 2 -CH 2 , CH 2 -C0, or C0-CH 2 . (A detailed discussion of the chemistry of non-peptide bonds is given in Coy et al. (1988) Tetrahedron 44.,3:835-841, hereby incorporated by reference, Tourwe (1985) Janssen Chim. Acta 2:3-15, 17-18, hereby incorporated by reference, and Spatola (1983) in Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins, (B. einstein, ed.) M. Dekker, New York and Basel, pp. 267-357," hereby incorporated by reference.) Preferably, analogs of the invention are 25% homologous, most preferably, 50% homologous, with the naturally occurring peptides. One modification of the naturally occurring peptide to create an antagonist is to employ, as the amino terminal residue, an aromatic D-isomer of an amino acid, or an alkylated amino acid. (Where "D" is not designated as the configuration of an amino acid, L is intended.) One class of peptide of the invention includes the substance P analogs of the formula: wherein ,1 = the D or L isomer of any one of the amino acids Arg, Lys, or Lys-€-NH-R (where R 2Q is any of H, C. , 2 alkyl, C ? _ 10 phenylalkyl, C0E 1Q (where E 1Q is C 1 _ 2Q alkyl, C_ 2Q alkenyl, C_ 20 alkinyl, phenyl, naphthyl, or C_ 1Q phenylalkyl) , or .-C^ acyl) ; or is deleted; A = the D or L isomer of the amino acid Pro; or is deleted; A = the D or L isomer of any one of the amino acids Lys, or Lys-e-NH-R 22 (where R 22 is any of H, C- _ 2 alkyl. C 7 _ 10 phenylalkyl, C0E 12 (where E 12 is C 1-20 alkyl, C 3 _ 2Q alkenyl, C 3-2Q alkinyl, phenyl, naphthyl, or C ? _ _ phenylalkyl) , or C 1 -C 12 acyl) ; or is deleted; A 4 = the D or L isomer of the amino acid Pro; or is deleted; A = the D or L isomer of any one of the amino acids Asp, Gin, β-Nal, Trp, Phe, o-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH 3 ), p-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH,); or is deleted; g J A = the D or L isomer of any one of the amino acids Ala, Arg, Ser, Pro, Gin, pGlu, Asn, β-Nal, Trp, Phe, o-X- Phe (where X = F, Cl, Br, N0 2 , OH, or CH 3 ) , or p-X- Phe (where X = F, Cl, Br, N0 2 , OH, or CH 3 ) ; A = the D or L isomer of any one of the amino acids Val, Thr, Phe, Trp, β-Nal, o-X-Phe (where X - F, Cl, Br, N0 2 , OH, or CH 3 ), or p-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH 3 ); A = the identifying group of the D or L isomer of any one of the amino acids Gly, Val, Trp, β-Nal, Phe, o-X-Phe (where X = F, Cl, Br, NO- , OH, or CHA , or p-X-Phe (where X - F, Cl, Br, NO , OH, or CH_) ; A 9 = the D or L i.somer of any one of the amm. o acids Sar, His, Gly, Trp, β-Nal, Phe, o-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH 3 ) , or p-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH 3 ); A = the identifying group of the D or L isomer of any one of the amino acids Trp, β-Nal, Leu, Nle, Ala, cyclσhexyl-Ala, Val, lie. Met, Gly, Phe, o-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH 3 ) , or p-X-Phe (where X - F, Cl, Br, NO,, OH, or CH_) ; A 11 = the identifying group of the D or L isomer of any one of the amino acids Trp, β-Nal, Leu, Nle, Ala, Val, lie, Met, Gly, Phe, o-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH 3 ), or p-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH 3 ); or is deleted; each R. and 2 , independently, is any of H, C 1-12 alkyl, C 7 ,_ phenylalkyl, COE 14 (where E χ4 is C wo alkyl, C-_ 20 alkenyl, C 3 . 20 alkinyl, phenyl, naphthyl, or C 7 _ 1Q phenylalkyl) , C_- C_ 2 acyl, or is deleted, and R. and 2 are bonded to the o-amino nitrogen atom of the N-terminal amino acid of said peptide, provided that, when one of R. or R 2 is COE- 4 , the other must be H; R 3 is H or C, 12 alkyl; R 5 is any one of CHZ 1() -(CH 2 ) nl -V , CH 2 -NH., CH 2 -S, CΑ-- CH 2 , CH 2 -CO, or CO-CH 2 (where V2 is either of - 8C-0-R ? or - IC-N AT *8 , R 9 (where each R ? , R g , and R g independently, is H, C 1-12 alkyl, C ? _ 10 phenylalkyl, or C 12 _ 2Q naphthylalkyl) ; nl is either 1 or 0; and Z 10 is either of H or OH) ; R g is C or and V is any of or deleted (where each R 1Q , R χι , and R _ independently, is H, C 1 _ 12 alkyl, C 7 _ 1Q phenylalkyl, or C 12 _ 2Q naphthylalkyl) ; provided that, where R g is CHZ 1() -(CH 2 ) nl -V 2 , A 11 , R g H, and V 1 must be deleted; further provided that, where A , R,H, and V 2 6 are deleted, g must be CHZ 1Q -(CH 2 ) nl -V ; further provided that, where A is Asp, A is Ser, A is Phe, A is Val, A is Gly, A is Leu, A 11 i.s Leu, and R g i.s CH 2 NH, at least one of A1, A , A3, or A must be present; or a pharmaceutically acceptable salt thereof. Another class of peptide of the invention includes the substance P analogs of the formula: wherein = the D or L isomer of any one of the amino acids Arg Lys, or Lys-e-NH-R gQ (where R g(J is any of H, C _ 12 alkyl, __ 1Q phenylalkyl, COE 2Q (where E 2Q is C 1-2Q alkyl, C 3 _ 2Q alkenyl, C 3 _ 2Q alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl) , or C^-C., acyl) ; or is deleted; A = the D or L isomer of the amino acid Pro; or is deleted; A 23 = the D or L isomer of any one of the ammo acids Lys or Lys-e-NH-R g2 (where R g2 is any of H, C χ _ 12 alkyl, C ? _ 10 phenylalkyl, COE 22 (where E 22 is C 1 _ 2Q alkyl, C 3 _ 2Q alkenyl, C 3 _ 2Q alkinyl, phenyl, naphthyl, or C_ 1Q phenylalkyl), or C.-C , acyl); or is deleted; A 24 = the D or L i.somer of the amm. o aci.d Pro; or is deleted; A 25 = the i.denti.fyi.ng group of the D or L isomer of any one of the amino acids Asp, Gin, β-Nal, Trp, Phe, o-X-Phe (where X - F, Cl, Br, N0 2 , OH, or CH 3 ) , p-X-Phe (where X = F, Cl, Br, NO_, OH, or CH_) ; or is deleted; A 26 = the identifying group of the D or L isomer of any one of the amino acids Arg, Sar, Pro, Gin, pGlu, Phe, Trp, cyclohexyl-Ala, or Asn; A 27 = the i.denti.fyi.ng group of the amino acid D-Trp; or the identifying group of the D or L isomer of any of Leu, Phe, or cyclohexyl-Ala; or is deleted; A 28 = the identifying group of the D or L isomer of any one of the amino acids Val, β-Nal, Phe, o-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH 3 ) , or p-X-Phe (where X = F, Cl, Br, NO,, OH, or CH,) ; or is deleted; A 29 = the identifying group of the amino acid D-Trp; or the identifying group of the D or L isomer of any of Leu, Phe, or cyclohexyl-Ala; A 30 = the identifying group of the D or L isomer of any one of the amino acids Leu, Nle, Ala, cyclohexyl-Ala, Val, lie, Met, Gly, Phe, Trp, β-Nal, o-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH 3 ), or p-X-Phe (where X = F, Cl, Br, NO,, OH, or CHA ; or is deleted; A _ _ = the identi.fyi.ng group of the D or L isomer of any one of the amino acids Trp, β-Nal, Leu, Nle, Ala, Val, lie. Met, Gly, Phe, o-X-Phe (where X = F, Cl, Br, NO , OH, or CH 3 ), or p-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH_) ; or is deleted; each R 51 and 52 , independently, is any of H, C 1 _ 12 alkyl, C phenylalkyl, COE 24 (where E 24 is C 1-20 alkyl, C 3 _ 2Q alkenyl, C 3 _ 20 alkinyl, phenyl, naphthyl, or C η _ 1Q phenylalkyl), C^-C^ acyl, or is deleted, and R g . and R g are bonded to the α-amino nitrogen atom of the N-terminal amino acid of said peptide, provided that, when one of R 51 or R g2 is C0E 24 , the other must be H; R g3 is C, or is deleted; each R 55 and R gl , independently is C; each R 57 R 5 9 ' R 6 3 ' and R 6 5' i nde P endentl Y/ i s either of C or deleted; R 54 is CO-NH, CO-NCH, _, or is deleted; each RJ c/ O. and R6,2,, independently, is any of CO-NH, CHZ 2£) -(CH 2 ) nl0 -CO-NH (where nlO is either 1 or 0; and Z 2Q is either of H or OH), CH -NH, CH 2 -S, CH 2 -CH 2 , CH 2 -CO, or CO-CH 2 ; R 5g is any of CO-NR 69 (where R 6g is H or C^^ alkyl), CHZ 20 -(CH 2 ) nl() -CO-NH, CH 2 -NH, CH 2 -S, CH 2 ~CH 2 , CH 2 ~CO, CO-CH 2 , or deleted; R g0 is CO-NH, or deleted; R g . is any of CO-NH, CHZ 2Q -(CH 2 ) nl0 - V 12 , CH 2 -NH, CH 2 -S, CH 2 -CH 2 , CH 2 -C0, CO-CH 2 , or deleted (where V is either of (where each R 7Q , R ?1 , and R ?2 independently, is H, C._ 12 alkyl, 10 7 - 10 P^eπy 131 ^ 1 / or c i 2 - 20 "a ^^Y 131 ^ 1) and v is any of or deleted (where each R gg , R β 7 ' and R 68 ind pendently, * s H c ι _ 12 alkyl , C 7-10 phenylalkyl, or C 12 _ 20 naphthylalkyl) ; provided that, at least one of 56 , R 58 ' R 62 ' or R 64 s other than either CO-NH or CO-NRo, ft y;,f_urther provided that, where Ro_o- is CHZ __ Λ V- (CH ) nlQ -CO-NH, A , R 52 H, and R gg must be deleted; further provided that, where A , 57 -H, and R gg are deleted, R_ g must be CHZ 20 -(CH 2 ) nl0 -CO-NH; further provided that, where R 5g is CHZ 2Q - (CH 2 ) nl0 -CO-NH, A 28 , R ςq H, and R g0 must be deleted; further provided that, where A , R 5g H, and R gQ are deleted, R 5g must be CHZ 20 -(CH 2 ) nl0 -C0-NH; further provided that, where R g2 is CHZ - (CH 2 ) nlQ -CO-NH, A 30 , R g3 H, and R g4 must be deleted; further provided that, where A , R 63 H, and R g are deleted, R g must be CHZ _ n U-(CH_ _)- Ω±- n O-C_O.-NH; further p.r-ovided that, where RD-4, is CHZ20 Λ - (CH,) n1 -v", A J± , R fiR H, and V ±u must be deleted; further provi .ded that, where A31, R 65 H, and V10 are deleted, R g4 must be CHZ 2Q -(CH 2 ) 1Q -V ; or a pharmaceutically acceptable salt thereof. Examples of preferred peptides are: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu L [CH 2 -NH]Leu-NH 2 ; D-Arg- Pro-Lys-Pro-Gln-Gln-D-Trp-Phe-D-Trp L [CH 2 -NH]Leu-Nle-NH 2 ; or D- Arg-Pro-Lys-Pro-Gln-Gln-D-Trp-Phe-D-Trp-LeuL [CH 2 -NH]Nle-NH 2 . (Non-peptide bonds in which the peptide bond is reduced are symbolized herein by "4cH 2 -NH]" or ""-"]. In another aspect the invention features a substance P agonist of the formula: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly [CH 2 -NH]Leu-Leu-NH 2 . SP antagonists of the invention are useful in the treatment of a patient suffering from diseases involving neurogenic inflamation e.g., rheumatoid arthritis, ulcerative colitis, eczema, and Crohn's disease. The SP antagonists of the invention are useful as antiproliferative agents e.g., in the treatment of small cell lung carcinoma or disorders involving the proliferation of fibroblasts. The antiproliferative properties of the SP antagonists of the invention also allow their use in the prevention of glial scarring (thus facilitating nerve regeneration) . The action of the antagonists of the invention on neurotransmission allow their use as nonopiate analgesics. Their use as nonopiate analgesics can permit the restoration of opiate response. The antagonists of the invention are also useful as antisecretory agents, acting e.g., on the salivary glands or on the pancreas. In the generic formulas given above, when any of R. , 2' V R 13' R 51' R 52' R 66 "R 68' ° r R 7θ "R 72 is an aromatic ' lipophilic group, the in vivo activity can be long lasting, and delivery of the compounds of the invention to the target tissue can be facilitated. The identifying group of an α-amino acid (for case of pyroglutamate, see below) is the atom or group of atoms, other than the α-carbonyl carbon atom, the α-amino nitrogen atom, or the H atom, bound to the asymmetric α-carbon atom. To illustrate by examples, the identifying group of alanine is CH,, the identifying group of valine is (CH 3 ) 2 CH, the identifying group of lysine is H 3 N (CHA and the identifying group of phenylalanine is (C g H g )CH 2 . The identifying group of a β- or γ-amino acid is the analagous atom or group of atoms bound to respectively, the β- or the γ-carbon atom. Where the identifying group of an amino acid is not specified it may be , β, or γ. In the case of pyroglutamate the identifying group consists of -NH-C0-CH,-CH_-. Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims. Description of the Preferred Embodiments We first briefly describe the drawings. Drawings Fig. 1 is a pair of graphs illustrating the effect of pseudopeptides of spantide, D-Arg-Pro-Lys-Pro-Gln-Gln-D-Trp-Phe- D-Trp-Leu-Leu-NH 2 , (left panel) and of SP, Arg-Pro-Lys-Pro-Gln- Gln-Phe-Phe-Gly-Leu-Met-NH , (right panel) on SP- stimulated amylase release from pancreatic acini. Fig. 2 is a graph showing the effect of Arg-Pro-Lys- Pro-Gln-Gln-Phe-Phe-Gly-Leu L[CH 2 -NH]Leu-NH 2 on SP-stimulated amylase release from pancreatic ancini . Fig. 3 is a pair of graphs illustrating the ability of various SP and spantide pseudopeptides to inhibit binding of 125 I-BH-substance P to pancreatic ancini. Fig. 4 is a graph showing the ability of SP and spantide pseudopeptides to inhibit binding of I-[Tyr ] bombesin to pancreatic acini. We now describe the structure, synthesis, and use of preferred embodiments of the invention. Structure The peptides of the invention all have modifications, e.g., a non-peptide bond in at least one of the indicated positions in which the carbon atom participating in the bond between two residues is reduced from a carbonyl carbon to a methylene carbon. The peptide bond reduction method which yields this non-peptide bond is described in Coy et al., U.S. patent application, Serial No. 879,348, assigned to the same assignee as the present application, hereby incorporated by reference. The peptides of the invention can be provided in the form of pharmaceutically acceptable salts. Examples of preferred salts are those with therapeutically acceptable organic acids, e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, salicylic, methanesulfonic, toluenesulfonic, or pamoic acid, as well as polymeric acids such as tannic acid or carboxymethyl cellulose, and salts with inorganic acids such as the hydrohalic acids, e.g., hydrochloric acid, sulfuric acid, or phosphoric acid. Synthesis of Substance P Analogs The synthesis of the substance P antagonist Arg-Pro- Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu » _[CH 2 NH]Leu-NH 2 follows. Other substance P analogs can be prepared by making the appropriate modifications of the following synthetic method. The first step is the preparation of the intermediate Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu L [CH 2 -NH]Leu- benzhydrylamine resin, as follows. Benzhydrylamine-polystyrene resin (Vega Biochemicals, Inc.) (0.97 g, 0.5 mmole) in the chloride ion form is placed in the reaction vessel of a Beckman 990B peptide synthesizer programmed to perform the following reaction cycle: (a) methylene chloride; (b) 33% trifluoroacetic acid (TFA) in methylene chloride (2 times for 1 and 25 min. each) ; (c) methylene chloride; (d) ethanol; (e) methylene chloride; and (f) 10% triethylamine in chloroform. The neutralized resin is stirred with alpha-t- butoxycarbonyl(Boc)-leucine and diisopropylcarbodiimide (1.5 mmole each) in methylene chloride for 1 hour, and the resulting amino acid resin is then cycled through steps (a) to (f) in the above wash program. Boc-leucine aldehyde (1.25 mmoles), prepared by the method of Fehrentz and Castro, Synthesis, p. 676 (1983) , is dissolved in 5 ml of dry dimethylformamide (DMF) and added to the resin TFA salt suspension followed by the addition of 100 mg (2 mmoles) of sodium cyanoborohydride (Sasaki and Coy, Peptides t$:119-12l (1987); Coy et al., id.). After stirring for 1 hour, the resin mixture is found to be negative to ninhydrin reaction (1 min.), indicating complete derivatization of the free amino group. The following amino acids (1.5 mmole) are then coupled successively in the presence diisopropylcarbodiimide (1.5 mmole), and the resulting amino acid resin is cycled through washing/deblocking steps (a) to (f) in the same procedure as above: Boc-Gly (Boc-Gly is coupled as a 6M excess of the p- nitrophenylester) , Boc-Phe, Boc-Phe, Boc-Gln, Boc-Gln, (Boc-Gln is coupled as a 6 M excess of the p-nitrophenylester) , Boc-Pro, Boc-Lys, Boc-Pro, and Boc-Arg. The completed resin is then washed with methanol and air dried. The resin described above (1.6 g, 0.5 mmole) is mixed with anisole (5 ml) and anhydrous hydrogen fluoride (35 ml) at 0°C and stirred for 45 min. Excess hydrogen fluoride is evaporated rapidly under a stream of dry nitrogen, and free peptide is precipitated and washed with ether. The crude peptide is dissolved in a minimum volume of 2 M acetic acid and purified on a column (2.5 x 90 cm) of Sephadex G-25 which is eluted with 2 M acetic acid, followed by preparative medium pressure chromatography on a column (1.5 x 45 cm) of Vydac Cl,o_ silica (10- 15 μm) which is eluted with linear gradients of acetonitrile in 0.1% trifluoroacetic acid using an Eldex Chromatrol gradient controller (flow rate 1 ml/min) . Where necessary, analogues are further purified by re-chromatography on the same column with slight modifications to the gradient conditions when necessary. Homogeneity of the peptides was assessed by thin layer chromatography and analytical reverse-phase high pressure liquid chromatography, and purity was 97% or higher. Amino acid analysis gave the expected amino acid ratios. The presence of the reduced peptide bond was demonstrated by fast atom bombardment mass spectrometry. Each of the analogues gave good recovery of the molecular ion corresponding to the calculated molecular mass. A statine, AHPPA, ACHPA, β-amino acid, or γ-amino acid residue is added in the same way as is a natural α-amino acid residue, by coupling as a Boc-amino acid. Statine or Boc-statine can be synthesized according to the method of Rich et al., 1978, J. Org. Chem. 43; 3624; Rich et al. (1988) J. Org. Chem. 53:869: and Rich et al., 1980, J. Med. Chem. ,23.:27. AHPPA can be synthesized according to the method of Hui et al., 1987, J. Med. Chem. .30:1287. ACHPA can be synthesized according to the method of Schuda et al., 1988, Journal of Organic Chemistry ≤2:873. Boc-coupled synthetic amino acids are avilable from Nova Biochemicals (Switzerland) , Bachem (Torrance, California) , and CalBiochem (San Diego, California) . Other compounds can be prepared as above and tested for effectiveness as agonists or antagonists in the following test program. Phase 1- Amylase Release From Par-,-;reatic Acini SP stimulates the relt e of amylase in pancreatic acini. The stimulation or inhib-.cion of release of amylase by pancreatic acini is used as a measure of, respectively, the agonist or antagonist activity of a peptide. Dispersed acini from the pancreas of one animal are suspended in 150 ml of standard incubation solution. Amylase release is measured as described previously (Gardner et al. (1977) J. Physiol. 270: 39) . Amylase activity is determined by the methods of Ceska et al. (Ceska et al. (1969) Clin. Chim. Acta. 2j>:437 and Ceska et al. (1969) Clin. Chim. Acta. .2.6:445) using the Phadebas reagent. Amylase release is calculated as the percentage of the amylase activity in the acini at the beginning of the incubation that was released into the extracellular medium during the incubation. PPhhaassee 22 - Competitive Inhibition of 125I-Bolton-Hunter-SP Binding Binding of 125 I-Bolton-Hunter-SP ( 125 I-BH-SP) to dispersed pancreatic acini is measured as described previously (Jensen et al. (1984) Biochem. Biophys. Acta. 804:181 and Jensen et al. (1988) Am. J. Physiol. 254:G883) . Incubations contain 0.125 nM 125I-BH-SP and 0.1% bacitracm in standard incubation buffer and were for 30 min at 37°C. Nonsaturable binding of 125 I-BH-SP i.s the amount of radi.oacti.vi.ty associated with the acini when the incubation contains 0.125 nM 125I-BH-SP plus 1 μM unlabeled SP. All values given are for saturable binding, i.e., binding measured with 125I-BH-SP alone (total bi.ndi.ng) . In all experiments nonsaturable binding was < 30% of total binding. Phase 3- Competitive Inhibi .ti.on of 125I-fTyr—41 Bombesi.n Bi.ndi.ng 125 I-[Tyr4] Bombesi.n (2200 Ci./mmol) i.s prepared using a modification of the method described previously (Jensen et al. (1978) Proc. Natl. Acad. Sci. USA 7_5:6139). Iodo-Gen (mg) is dissolved in 5 ml of chloroform and 5 μl of this solution (1 μg Iodo-Gen) is transferred to a vial under a stream of nitrogen. To this vial 50 μl of KH PO (pH 7.4), 6 μg [Tyr 4 ]bombesin in 5 μl water and 1 mCi Na 125I i.s added, mi.xed and i.ncubated for 6 min at 4°C, at which time the iodination mixture is added to a vial of 1 M dithiothreitol and incubated at 80°C for 60 min. The iodination mixture is then loaded onto a Sep-Pak cartridge and eluted with 0.25 M tetraethylammonium phosphate (TEAP) followed 1 __ V_ A by 50% (vol/vol) acetonitrile-0.25 M TEAP. I-[Tyr ]bombesin is purified using reverse-phase high-performance liquid chromatography (HPCL) and eluted. Results of Assays of Test Peptides A number of analogues of substance P, or of " the substance P antagonist spantide, each containing a non-peptide bond, can be synthesized and tested in one or more of the assays described in Phase 1 - Phase 3 above. The structure of substance P is Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met- NH 2 . Spantide is an analog of SP. The structure of spantide is D-Arg-Pro-Lys- Pro-Gln-Gln-D-Trp-Phe-D-Trp-Leu-Leu-NH 2 . Stimulation or inhibition of the release of amylase from dispersed pancreatic acini was used as an assay for SP agonist activity or SP antagonist activity respectively. At a concentration of 10 μM, 9 of 10 SP and spantide derived pseudopeptides failed to stimulate amylase release when present alone (Table 2) . One peptide, Arg- Pro-Lys-Pro-Gln-Gln-Phe-Phe- Gly [CH 2 ~NH]Leu-Leu-NH , (10 μM) had agonist activity causing a 3-fold increase in amylase release (Table 2) . Each of the 9 pseudopeptides without agonist activity was examined for activity as a SP antagonist. At a concentration of lOμM each of the spantide derived pseudopeptide analogues inhibited 1 nM-SP-stimulated amylase release. (Table 2) Three SP pseudopeptides, Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe- Gly-Leu L [CH 2 -NH]Leu-NH 2 , Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe [CH - NH]Gly-Leu-Leu-NH 2 , and Arg-Pro-Lys-Pro-Gln-Gln [CH 2 -NH]Phe-Phe- Gly-Leu-Leu- NH 2 caused inhibition (Table 2) . The relative abilities of each peptide to inhibit SP- stimulated amylase release was determined by the effect of peptide dose on inhibition. Dose-inhibition studies were carried out for each of the 9 pseudopeptides using a concentration of SP (InM) that causes half-maximal stimulation. (Fig. 1) . Results for the 5 spantide derived pseudopeptides are shown in Fig. 1, left panel. D-Arg-Pro-Lys-Pro-Gln-Gln- D-Trp-Phe-D-Trp-Leu L [CH 2 - NH]Nle-NH 2 was equipotent to spantide, causing detectable inhibition at 0.03 μM and half-maximal inhibition at 1.8 μM (Table 3). D-Arg-Pro-Lys- Pro-Gln-Gln-D-Trp-Phe-D-Trp L [CH 2 - NH]Leu-Nle-NH 2 was 'J-fold less potent (IC 5Q 3.5 μM, Table 3) than spantide. D-Arg-P -Lys-Pro-Gln-Gln [CH 2 -NH]D-Trp-Phe-D-Trp- Leu-Nle-NH 2 was 2.6-times (IC 5Q 4.7 μM) less potent than spantide. D-Arg-Pro-Lys-Pro-Gln-Gln-D-Trp L [CH 2 -NH]Phe-D-Trp- Leu-Nle-NH 2 was 3.5-times (IC 50 , 6.4-μM) less potent and D-Arg— Pro-Lys-Pro-Gln-Gln-D-Trp-Phe L [CH 2 -NH]D-Trp-Leu-Nle-NH 2 was 17- times (IC 50 , 30 μM) less potent than spantide (Table 3). Results for the SP pseudopeptide analogues are shown in Fig. 1, right panel. Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly- Leu L [CH 2 -NH]Leu-NH 2 was the most potent SP derivative causing detectible inhibition at 0.3 μM and half-maximal inhibition at 7.1 μM (Table 3, right). Arg-Pro-Lys-Pro-Gln-Gln-Phe-PheL[CH 2 - NH]Gly-Leu- Leu-NH 2 and Arg-Pro-Lys-Pro-Gln-Gln [CH -NH]Phe-Phe- Gly-Leu-Leu-NH 2 were less effective, causing detectable inhibition at 10 μM. They are, respectively, 7-fold and 46-fold less potent than Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe- Gly-Leu [CH, _ * - NH]Leu-NH 2 (Table 3, right). Arg-Pro-Lys-Pro-Gln-Gln-PheL[CH 2 - NH]Phe-Gly-Leu-Leu-NH 2 exhibited no inhibitory activity at concentrations as high as 30 μM (Fig. 1, right) . The most potent SP derived pseudopeptide antagonist was Arg-Pro-Lys-Pro-Gln-Gln- Phe-Phe- Gly-Leu [CH 2 -NH]Leu-NH 2 (Fig. 1, Table 2). The inhibitory effects of the most potent SP derived pseudopeptide antagonist, Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly- Leu L [CH 2 -NH]Leu-NH 2 , are shown in Fig. 2. Acini were incubated with increasing concentrations of SP. Amylase release was detectible with 0.1 nM SP, was haIf-maximal with 1 nM SP2, and was maximal with 10 nM (Fig. 2) . Addition of Arg-Pro-Lys-Pro- Gln-Gln-Phe-Phe-Gly-Leu L [CH 2 -NH]Leu-NH 2 caused a parallel rightward shift in the dose-response curve for SP-stimulated amylase release. The shift was proportional to the concentration of Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly- Leu L [CH 2 -NH]Leu-NH 2 added but there was no change in the maximal response (Fig. 2) . D- Arg-Pro-Lys-Pro-Gln-Gln-D-Trp- Phe-D-Trp-Leu L [CH 2 -NH]Nle-NH 2 gave similar results (data not shown) . The interaction of SP and spantide derived analogues with the SP receptors of pancreatic acini was measured by the ability of a peptide to inhibit the binding of 125I-BH-SP to acini. (See Table 3 and Fig. 3.) The spantide derived pseudopeptides show a range of potencies. D-Arg-Pro-Lys-Pro-Gln-Gln-D-Trp-Phe-D-Trp-Leu [CH 2 NH]Nle-NH 2 is roughly equivalent in potency to spantide causing detectible inhibition at 0.03 μM and half-maximal inhibition at 2.2 μM (Fig. 3, left, Table 3). D-Arg-Pro-Lys- Pro-Gln-Gln-D-Trp-Phe-D-Trp [CH 2 -NH]Leu-Nle-NH 2 and D-Arg-Pro- Lys-Pro-Gln-Gln [CH 2 -NH]D-Trp-Phe-D-Trp- Leu-Nle-NH are 2-fold less potent than spantide. D-Arg-Pro-Lys-Pro-Gln-Gln-D-Trp [CH_- NH]Phe-D-Trp-Leu-Nle-NH 2 was 3-times (K., 6.3 μM) less potent than spantide. D-Arg-Pro-Lys-Pro-Gln-Gln-D-Trp-Phe [CH,-NH]D- Trp-Leu-Nle-NH 2 was 7-times (K., 14.7 μM) less potent than spantide (Fig. 3, Table 3). The SP derived pseudopeptides also show a range of potencies. Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu [CH 2 -NH]Leu- NH 2 causes detectable inhibition at 0.1 μM, and half-maximal inhibition at 3 μM. Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly L [CH,- NH]Leu-Leu-NH 2 is 1.5-fold lower in potency, Arg-Pro-Lys-Pro- Gln-Gln-Phe-Phe L [CH 2 -NH]Gly-Leu-Leu-NH 2 is 20-times less potent, and Arg-Pro-Lys-Pro-Gln-Gln-Phe [CH 2 -NH]Phe-Gly-Leu-Leu-NH 2 and Arg-Pro-Lys-Pro-Gln- Gln L [CH 2 -NH]Phe-Phe-Gly-Leu-Leu-NH 2 are more than 62-times less potent than Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe- Gly-LeuL[CH 2 -NH]Leu-NH 2 . Unlike previously studied SP analogs the peptides of the invention are specific to the SP receptor. Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu L [CH 2 -NH]Leu-NH 2 was tested for the ability to inhibit amylase release produced by various pancreatic secretagogues (Table 4) . Arg-Pro-Lys-Pro- Gln-Gln-Phe-Phe-Gly-LeuL[CH 2 -NH]Leu-NH 2 (20 μM) inhibited amylase release stimulated by SP, but did not alter bombesin, CCK-8, carbaσhol, VIP, secretin, CGR? A23187 or TPA stimulated amylase release. The most potent receptor antagonists were tested for their ability to inhibit the binding of I-[Tyr ] bombesin to the bombesin receptors of pancreatic acini. Spantide inhibited binding of 125I-[Tyr4] bombesin as reported previously (Jensen et al. (1988) Am. J. Physiol. 254:G883) causing half-maximal inhibition at 3 + 1 μM and complete inhibition at 100 μM (Fig. 4). D-Arg-Pro-Lys-Pro-Gln-Gln-D-Trp-Phe-D-Trp-Leu L [CH,- . : 125 4 NH] Nle-NH 2 inhibited I-[Tyr ] ombesin binding but was 3-fold less potent than spantide causing half-maximal inhibition at 10 μM (p < 0.05 compared to spantide) (Fig. 4). Arg-Pro-Lys-Pro- Gln-Gln-Phe-Phe-Gly-Leu>-[CH 2 -NH] Leu-NH 2 did not cause detectable inhibition until concentrations above 30 μM and had a calculated K. of 300 + 20 μM. Spantide and D-Arg-Pro-Lys-Pro-Gln-Gln-D- Trp-Phe-D- Trp-LeuL[CH -NH]Nle-NH_ had a 3- to 10-fold lower affi .ni.ty for i.nhi.bi.ti.ng 125I- [Tyr4]bombesin binding as compared to 125 I-BH-SP. The ability of Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu L [CH,- NH]Leu-NH 2 to inhi .bi.t bi.ndi.ng of 125I-[Tyr4] bombesin was 70- fold lower than i .ts abi.li.ty to inhibit binding of 125I-BH-SP. Use The peptides of the invention may be administered to a mammal, particularly a human, in one of the traditional modes (e.g., orally, parenterally, transdermally, or transmucosally) , in a sustained release formulation using a biodegradable biocompatible polymer, or by on-site delivery using micelles, gels and liposomes. The peptides can be administered to a human patient in a dosage of 0.5 μg/kg/day to 5 g/kg/day. Table 1. The five carboxy1-terminal residues of a variety of bioactive peptides. Peptide Carboxyl Terminal Sequence Bombesin -Val-Gly-His-Leu-Met-NH 2 Neuromedin-β -Thr-Gly-His-Phe-Met-NH 2 Neuromedin-C -Va1-Gly-His-Leu-Met-NH 2 Litorin -Val-Gly-His-Phe-Met-NH 2 Neurokinin-A -Phe-Val-Gly-Leu-Leu-NH 2 Neurokinin-B -Phe-Val-Gly-Leu-Met-NH 2 Substance P -Phe-Phe-Gly-Leu-Met-NH, Prototypical Tachykinin Sequence -Phe-X-Gly-Leu-Met-NH 2 (where X = a branched aliphatic or aromatic amino acid residue) 3 Table 2. Effect of the various SP and spantide derived pseudopeptides on basal and SP-stimulated amylase release Amylase Release (percent total) Peptide Added Alone SP (1 nM) None 3.4 ± 0.5 6.6 ± 0.7 Arg-Pro-Lys-Pro-Gln-Gln-Phe- 3.1 + 0.7 4.3 ± 0.5* Phe-Gly-LeuL[CH 2 -NH]Leu-NH 2 (lOμM) Arg-Pro-Lys-Pro-Gln-Gln-Phe- 10.4 + l.o** NT-agonist Phe-GlyL[CH 2 -NH]Leu-Leu-NH 2 (lOμM) Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe L 3.1 + 1.0 5.4 + 0.7* [CH 2 -NH]Gly-Leu-Leu-NH 2 (lOμM) Arg-Pro-Lys-Pro-Gln-Gln- 3.8 + 0.7 6.4 + 0.3 PheL[CH 2 -NH]Phe-Gly-Leu-Leu-NH 2 (lOμM) Arg-Pro-Lys-Pro-Gln-Gln [CH_-NH] 3.1 + 0.9 6.1 + 1.0* Phe-Phe-Gly-Leu-Leu-NH 2 (10#M) D-Arg-Pro-Lys-Pro-Gln-Gln-D- 3 ' .8 + 0.05 3.6 + 0.1* Trp-Phe-D-Trp-Leu L[CH 2 -NH]Nle-NH 2 (lOμM) D-Arg-Pro-Lys-Pro-Gln-Gln-D-Trp- 3.9 + 0.8 4.2 + 0.2* Phe-D-Trp L [ CH 2 -NH ] Leu-Nle-NH 2 ( 1 OμM) D-Arg. Pro-Lys-Pro-Gln-Gln-D-Trp- 4.0 + 0.5 5.6 + 0.8* Phe L[CH 2 -NH] D-Trp-Leu-Nle-NH 2 (lOμM) D-Arg-Pro-Lys-Pro-Gln-Gln-D-Trp L 4.1 + 0.5 4.8 + 1.2* [CH -NH]Phe-D-Trp-Leu-Nle-NH ( lOμM) D-Arg-Pro-Lys-Pro-Gln-Gln [CH -NH] 3 .8 + 0.3 4.5 ± 0.8* D-Trp-Phe-D-Trp-Leu-Nle-NH 2 (I OμM) * Significantly less than SP alone p < 0.05 ** Significantly greater than no additions p < 0.01 Acini were incubated at 37°C for 30 min with 1 nM SP and 10 μM concentrations of the various SP and spantide pseudopeptide analogues either alone or in combination. Amylase release was expressed as percent of amylase activity in acini at the start of incubation that was released into extracellular medium during incubation. Values are means + 1SEM from at least 5 separated experiments. In each experiment, each value was determined in duplicate. Abbreviations: NT-agonist = Not tested as an antagonist because it was an agonist. Table 3. Abilities of SP, spantide and pseudopeptide to inhibit binding of I-BH-SP or SP-stimulated amylase release. Inhibition of 1251-BH-sp INmsp-stimulated Peptide Binding Amylase Release K. or K,(μM) IC_ n (μM) D-Arg-Pro-Lys-Pro-Gln-Gln-D-Trp- α su Phe-D-Trp-Leu-Leu-NH 2 (Spantid 2.1 + 0.6 1.8 + 0.1 D-Arg-Pro-Lys-Pro-Gln-Gln-D-Trp- Phe-D-Trp-Leu>-[CH 2 NH]Nle-NH 2 2.2 + 0.4 1.8 ± 0.25 D-Arg-Pro-Lys-Pro-Gln-Gln-D-Trp- Phe-D-Trp L [CH 2 -NH] Leu-Nle-NH 2 3 . 6 + 0 .7 3 .5 ± 0. 6 D-Arg-Pro-Lys-Pro-Gln-Gln-D-Trp- Phe L [CH 2 -NH]D-Trp-Leu-Nle-NH 2 14.7 + 2.0 30 + 5.0 D-Arg-Pro-Lys-Pro-Gln-Gln-D-Trp L [CH 2 -NH]Phe-D-Trp-Leu-Nle-NH 2 6.3 ± 3.3 6.4 + 1.4 D-Arg-Pro-Lys-Pro-Gln-Gln L [CH_-NH]D-Trp-Phe-D-Trp-Leu-Nle- NH 2 ^ 4.3 ± l.l 4.7 + 1.3 Arg-Pro-Lys-Pro-Gln-Gln-Phe- Phe-Gly-Leu-Met-NH 2 (SP) 0.0025 + 0.0005 No-Agonist Arg-Pro-Lys-Pro-Gln-Gln-Phe- Phe-Gly-Leu L [CH 2 -NH]Leu-NH 4.3 + 0.3 7.1 + 0.9* Arg-Pro-Lys-Pro-Gln-Gln-Phe- Phe-Gly [CH 2 -NH]Leu-Leu-NH 5.6 + 2.2 No-Agonist Arg-Pro-Lys-Pro-Gln-Gln-Phe- PheL[CH 2 -NH]Gly-Leu-Leu-NH 2 41.3 +16.7 >30 Arg-Pro-Lys-Pro-Gln-Gln-Phe L [CH 2 -NH]Phe-Gly-Leu-Leu-NH 2 2«5.0 + 89.0 >30 Arg-Pro-Lys-Pro-Gln-Gln L [CH - NH]Phe-Phe-Gly-Leu-Leu-NH 2 A .π _- 88.0 >30 Values are means + 1SEM, 5 Kd values for SP are obtained from Scatchard analysis of I-labeled SP binding studies K. values for agonist or antagonists from studies of binding I-BH-SP were obtained according to the equation: K. = R/l-R) (SB/S+A) where R is tL ^ observed saturable binding or I-BH-SP in the presence of antagonist (B) expressed as a fraction of that 12ς obtained when B is not present; A is the concentration of 125 ι- BH-SP (0.125 nM) . B is the concentration of antagonist, S is the K, of SP determined by Scatchard analysis. No-agonist = peptide not tested for inhibition activity because agonist activity when present alone. Table 4. Ability of Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu [CH 2 -NH]Leu-NH 2 to affect amylase release stimulated by various secretagogues. Amylase Release (percent total) Alone Leu , Lio-ll-SP Secretagocrue (20 uM) None 2.7 + 0.4 2.3 + 0.3 Substance P (1 nM) 8.7 + 1.8 4.3 + 0.5* CCK-8 (0.1 nM) 19.7 ± 4.2 21.6 + 4.9 Bombesin (0.3 nM) 14.8 + 4.1 14.3 + 3.1 Carbachol (10 μM) 22.7 + 4.1 20.7 + 4.3 VIP (0.3 nM) 20.5 + 3.5 18.9 + 4.2 Secretin (0.1 μM) 18.9 ± 3.6 18.8 + 4.1 CGRP (0.1 μM) 12.1 + 3.3 12.0 + 3.9 A23187 (0.1 μM) 9.9 + 1.5 11.6 + 1.6 TPA (0.1 μM) 32.2 + 5.7 30.2 + 5.6 *Significantly less than secretagogue alone p < 0.001 Acini were incubated for 30 min at 37°C with various pancreatic secretagogues alone or with Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe- Gly-Leu [CH 2 -NH]LeuNH 2 . In each experiment, each value was determined in duplicate, and results give means + 1SEM from at least 4 separated experiments. Abbreviations: CCK-8, COOH- terminal octapeptide of cholecystokinin; VIP, vasoactive intestinal peptide, respectively; CGRP, calcitonin gene-related peptide; A23187 and TPA, l,2-o-tetradecanoylphorbol-l,3-acetate. Other Embodiments Other embodiments are within the following claims. What is claimed is:

Claims: Claims 1. A linear peptide which is an analog of naturally occurring, biologically active substance P having an active site and a binding site responsible for the binding of said peptide to a receptor on a target cell, said analog having one of the following modifications, (a) a non-peptide bond instead of a peptide bond between an amino acid residue of said active site and an adjacent amino acid residue, (b) a statine or AHPPA or ACHPA or β-amino acid or γ-amino acid residue in place of two naturally occurring amino acid residues of said active site, (c) a deletion of an amino acid residue within the active site and a modification of an amino acid residue outside the active site, or (d) the presence of an N-terminal amino acid residue that is not the natural N-terminal amino acid residue of said naturally occurring, biologically active peptide. 2. A linear peptide, which is an analog of substance P, of claim 1 wherein said analog is capable of binding to said receptor, so that said analog is capable of acting as a competitive inhibitor of said naturally occurring peptide by binding to said receptor and, by virtue of one of said modifications, failing to exhibit the m vivo activity of said naturally occurring peptide. 3. A linear peptide of claim 1 wherein said active site of said linear peptide is in the carboxyl terminal-half of said linear peptide, said linear peptide having one of the following modifications, (a) a non-peptide bond instead of a peptide bond between an amino acid residue of said active site and an adjacent amino acid residue, (b) a statine or AHPPA or ACHPA or β-amino acid or γ-amino acid residue in place of two naturally occurring amino acid residues of said active site, (c) a deletion of an amino acid residue within the active site and a modification of an amino acid residue outside the active site, or (d) the presence of an N-terminal amino acid residue that is not the natural N-terminal amino acid residue of said naturally occurring, biologically active peptide. 4. A linear peptide of claim 1 wherein said active site of said linear peptide is in the carboxyl terminal-half of said linear peptide, said linear peptide having one of the following modifications, (a) a non-peptide bond instead of a peptide bond between the carboxyl terminal amino acid residue and the adjacent amino acid residue, or (b) a statine or AHPPA or ACHPA or β- amino acid or γ-amino acid residue in place of the naturally occurring carboxyl terminal and adjacent amino acid residues. 5. A linear peptide of claim 1 wherein said linear peptide is an analog of naturally occurring, biologicall active substance P, said analog having one of the following modifications, (a) a non-peptide bond instead of a peptide bond between an amino acid residue of said active site and an adjacent amino acid residue, or (b) a statine or AHPPA or ACHPA or β- amino acid or γ-amino acid residue in place of two naturally occurring amino acid residues of said active site. 6. The substance P analog of claim 5 wherein said analog is at least 25% homologous with naturally occurring substance P. 7. The substance P analog of claim 5 wherein said analog is at least 50% homologous with naturally occurring substance P. 8. The substance P analoα A claim 5 of the formula: wherein .1 = the D or L isomer of any one of the amino acids Arg, Lys, or Lys-e-NH-R (-..-here R ~ is any of H, C._ 12 alkyl, C 7 _ 10 phenylalkyl, COE 10 (where E 1Q is C 1 _ 2 Q alkyl, C 3 _ 2fJ alkenyl, C 3 _ 2Q alkinyl, phenyl, naphthyl, or C_ 10 phenylalkyl) , or C_ ~C 12 a °y^ ' or ^ s deleted; A = the D or L isomer of the amino acid Pro; or is deleted; _> A = the D or L isomer of any one of the amino acids Lys, or Lys-e-NH-R 22 (where R is any of H, C- ,_ alkyl, C 7-1 0 P hen y la lkyl, C0E i2 (whe e E 12 * s C ι-20 alk -Y '1 ' C 3-20 alken V 1 ' C 3-2 0 alkin 1 ' Phenyl, naphthyl, or C_ 10 phenylalkyl) , or 1 ~C acyl) ; or is deleted; A = the D or L isomer of the amino acid Pro; or is deleted; A 5 = the D or L i.somer of any one of the amm. o acids Asp, Gin, β-Nal, Trp, Phe, o-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH 3 ), p-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH ) ; or is deleted; A = the D or L isomer of any one of the amino acids Ala, Arg, Ser, Pro, Gin, pGlu, Asn, β-Nal, Trp, Phe, o-X- Phe (where X = F, Cl, Br, N0 2 , OH, or CH 3 ), or p-X- Phe (where X = F, Cl, Br, NO , OH, or CH_); A 7 = the D or L i.somer of any one of the amm. o aci.ds Val, Thr, Phe, Trp, β-Nal, o-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH 3 ), or p-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH 3 ) ; A = the identifying group of the D or L isomer of any one of the amino acids Gly, Val, Trp, β-Nal, Phe, o-X-Phe (where X = F, Cl, Br, Nθ 2 , OH, or CH 3 ) , or p-X-Phe (where X = F, Cl, Br, NO,, OH, or CH ) ; A 9 = the D or L isomer of any one of the amino acids Sar, His, Gly, Trp, β-Nal, Phe, o-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH 3 ), or p-X-Phe (where X = F, Cl, Br, NO,, OH, or CH ) ; A 10 = the i.denti.fyi.ng group of the D or L isomer of any one of the amino acids Trp, β-Nal, Leu, Nle, Ala, cyclohexyl-Ala, Val, lie, Met, Gly, Phe, o-X-Phe (where X = F, Cl , Br , N0 2 , OH, or CH 3 ) , or p-X-Phe (where X = F, Cl, Br, NO , OH, or CHA ; A11 = the identifyi.ng group of the D or L isomer of any one of the amino acids Trp, β-Nal, Leu, Nle, Ala, Val, He, Met, Gly, Phe, o-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH 3 ), or p-X-Phe (where X = F, Cl, Br, NO , OH, or CH 3 ) ; or is deleted; each R χ and R 2 , independently, is any of H, C. _ 12 alkyl, c_ Q phenylalkyl, COE 14 (where E 14 is C 1 _ 2Q alkyl, C 3 _ 2Q alkenyl, C 3 _ 20 alkinyl, phenyl, naphthyl, or C-_ 1Q phenylalkyl), C 1 -C 12 acyl, or is deleted, and R. and R are bonded to the α-amino nitrogen atom of the N-terminal amino acid of said peptide, provided that, when one of R. or R 2 is COE- 4 , the other must be H; R is H or C l-12 alk y 1 ' R 5 is an one of CHZ 10~ (CH 2 ) nl "v2 ' CH 2~ NH ' CH 2 _S ' CH 2 -CH 2 , CH 2 -CO, or CO-CH 2 (where V 2 is either of (where each R- , R g , and R independently, is H, C. , 2 alkyl, C_ 1Q phenylalkyl, or 12 _ 2() naphthylalkyl); nl is either 1 or 0; and Z5. 1n iiss eeiitthheerr ooff HH oorr OOHH)) ;; RR is C or and V is any of or deleted (where each R 10 , R n > and R i2 independently, is H, C_ 12 alkyl, C_ _ phenylalkyl, or C __ Q naphthylalkyl); provided that, where R5 κ is CHZ 1 1 Λ 0-(CH2A„n.l-V 2 , A ,' R Λ 6H, and V 1 m-ust be deleted; further provided that, where A , R,H, and V are deleted, R_ must be CHZ --(CH.) .-V 2; further provided that, where A is Asp, A is Ser, A is Phe, A is Val, A is Gly, A is Leu, A 11 i.s Leu, and R_ i.s CH,NH, at least one of A1 , A , A3 , or A 4 must be present; or a pharmaceutically acceptable salt thereof. 9. The substance P analog of claim 5 of the formula: wherein = the D or L isomer of any one of the ammo acids Arg Lys, or Lys-e-NH-R (where R Q is any of H, C ± , 2 alkyl, C 7 _ 10 phenylalkyl, C0E 2Q (where E 2Q is C 1 _ 2Q alkyl, C 3 _ alkenyl, C 3 _ alkinyl, phenyl, naphthyl, or C_ 10 phenylalkyl) , or C -C acyl) ; or is deleted; A = the D or L isomer of the amino acid Pro; or is deleted; A 23 = the D or L i.somer of any one of the amm. o aci.ds Lys or Lys-e-NH-R (where R is any of H, C, 12 alkyl, C_ 10 phenylalkyl, C0E 22 (where E 22 is C 1 _ 2Q alkyl, C 3 _ 2Q alkenyl, C 3 _ 2( _ alkinyl, phenyl, naphthyl, or - , Q phenylalkyl), or C -C acyl); or is deleted; 24 . . . A = the D or L isomer of the am o acid Pro; or is deleted; 25 . . . A = the identifying group of the D or L isomer of any one of the amino acids Asp, Gin, β-Nal, Trp, Phe, o-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH 3 ) , p-X-Phe (where X = F, Cl, Br, NO , OH, or CH ) ; or is deleted; A 26 = the identifying group of the D or L isomer of any one of the amino acids Arg, Sar, Pro, Gin, pGlu, Phe, Trp, cyclohexyl-Ala, or Asn; 27 . . . . . A = the identifying group of the ammo acid D-Trp; or the identifying group of the D or L isomer of any of Leu, Phe, or cyclohexyl-Ala; or is deleted; A 28 = the identifying group of the D or L isomer of any one of the amino acids Val, β-Nal, Phe, o-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH 3 ) , or p-X-Phe (where X = F, Cl, Br, NO,, OH, or CH 3 ); or is deleted; A?9 = the identi .fyi .ng group of the amm . o acid D-Trp; or the identifying group of the D or L isomer of any of Leu, Phe, or cyclohexyl-Ala; A = the identifying group of the D or L isomer of any one of the amino acids Leu, Nle, Ala, cyclohexyl-Ala, Val, He, Met, Gly, Phe, Trp, β-Nal, o-X-Phe (where X - F, Cl, Br, N0 2 , OH, or CH 3 ), or p-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH ) ; or is deleted; A = the identifying group of the D or L isomer of any one of the amino acids Trp, β-Nal, Leu, Nle, Ala, Val, He, Met, Gly, Phe, o-X-Phe (where X = F, Cl, Br, NO, __, OH, or CH 3 ), or p-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH_) ; or is deleted; each R 51 and R 52 , independently, is any of H, C^ ,. alkyl, C_ 1Q phenylalkyl, COE 24 (where E 24 is _ 2 Q alkyl, C 3 _ 2Q alkenyl, C 3 _ 20 alkinyl, phenyl, naphthyl, or C-_ 1Q phenylalkyl), ^-C^ acyl, or is deleted, and R 5 and R are bonded to the α-amino nitrogen atom of the N-terminal amino acid of said peptide, provided that, when one of R 51 or R 52 is C0E_ 4 , the other must be H; R_, is C, or is deleted; each R 55 , and R g , independently is C; each R ς7 R_ g , R g3 nd R g5/ independently, is either of C or deleted; R . is CO-NH, CO-NCH,, or is deleted; each R..,, and R,,,, independently, is any of CO-NH, CHZ 2(J -(CH 2 ) 10 -CO r NH (where nlO is either 1 or 0; and Z _ is either of H or OH), CH 2 -NH, CH 2 ~S, CH 2 -CH 2 , CH 2 -C0, or CO-CH 2 ; R 5g is any of CO-NR gg (where R gg is H or C 1 _ 12 alkyl)', CHZ 2Q -(CH 2 ) nlQ -C0-NH, CH 2 ~NH, CH 2 -S, C^-CH.,, CH 2 ~CO, CO-CH 2 , or deleted; R Q is CO-NH, or deleted; R g is any Of CO-NH, CHZ 20 -(CH 2 ) nl0 - V 12 , CH 2 ~NH, CH 2 -S, CH 2 -CH 2 , CH 2 -CO, CO-CH 2 , or deleted (where V is either of (where each R ?0 , R ?1 , and R ?2 independently, is H, C 1 _ 12 alkyl, C 7 - 10 P he nylalkyl, or c 12 - 20 na P ht hylalkyl) ; and V 10 is any of or deleted (where each R g6 , R 67 and R g8 independently, is H, C, 12 alkyl, C_, , Q phenylalkyl, or C 12 _ naphthylalkyl) " ; provided that, at least one of R 5g , R 58 , R g , or R . is other than either CO-NH or CO-NR,>„y;,f_urther provided that, where s C o /r is CHZ_ _ n U- (CH 2 ) nl0 -CO-NH, A , R 52 H, and R 58 must be deleted; further provided that, where A , R 57 H, and R g are deleted, R 5g must be CHZ 2Q -(CH 2 ) 1Q -CO-NH; further provided that, where R gg is CHZ 2Q - (CH 2 ) nl0 -CO-NH, A 28 , R πq H, and R 6Q must be deleted; further provided that, where A , 5g H »- and R 60 a e deleted. R g8 must be CHZ, _ n --(CH_ _ m.u.-CO-,N_H; further provided that, where R_ ___ is CHZ, ___- (CH_ _)n-u_-CO-NH, A , R Λ p,-iH, and R r ot Λ must be deleted; further provided that, where A , R 63 H, and R are deleted, R g2 must be thereof. 10. The substance P innleg of claim 9 of the formula: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly- Leu [CH 2 -NH]Leu-NH 2 ; 11. The substance r •-'Αgs of claim 10 of the formula: D-Arg-Pro-Lys-Pro-Glr- -A.-D-Trp-Phe- D-Trp L [CH 2 ~ NH]Leu-Nle-NH 2 ; or D-Arg-Pro-Lys-Pro-Glr:-An-ATrp-Phe-D-Trp- Leu [CH 2 - NH]Nle-NH 2

Inventors: COY DAVID H, MOREAU JACQUES-PIERRE, COY, DAVID, H., MOREAU, JACQUES-PIERRE
Applicants: UNIV TULANE, THE ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND
Application year: 1990
Main classification: C07K7
IPC codes: A61K38, C07K7