THERAPEUTIC PEPTIDES

Abstract: In general, the invention features a linear (i.e., non-cyclic) bombesin analog of biologically active mammalian gastrin-releasing peptide (GRP) and amphibian bombesin, having an active site and a binding site responsable for the binding of the peptide to a receptor on a target cell; cleavage of a peptide bond in the active site of naturally occuring bombesin or GRP is unnecessary for in vivo bilogical activity. The analog has one of the following modifications: (a) a deletion of a residue within the active site and a modification of a residue outside of the active site, or (b) a remplacement of one or two residues within the active site with a synthetic amino acid. The analog is capable of binding to the receptor and acting as a competitive inhibitor of the naturally occurring peptide 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.

Description: THERAPEUTIC PEPTIDES Background of the Invention This invention relates to therapeutic peptides useful, e.g., for treatment of benign or malignant proliferation of tissue and for gastrointestinal disorders. The amphibian peptide bombesin, pGlu-Gln-Arg- Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His- eu-Met-NH 2 (Anastasi et al. , Ξxperientia 22:166-167 (1971)), is closely related to the mammalian gastrin-releasing peptides (GRP), e.g., the porcine GRP, H_N- Ala-Pro-Val-Ser-Val-Gly-Gly-Gly-Thr- Val-Leu-Ala-Lys-Met-Tyr-Pro-Arg-Gly-Asn-His-Trp-Ala- Va1-Gly-His-Leu-Met-(NH,) (McDonald et al. , Biochem. Biophys. Res. Contmun. 9_0:227-233 (1979)) and human GRP, H 2 N-Val-Pro-Leu-Pro-Ala-Gly-Gly-Gly-Thr-Val-Leu-Thr-Lys- Met-Tyr-Pro-Arg-Gly-Asn-His-Trp-Ala-Val-Gly-His-Leu-Met (NH_) . Bombesin has been found to be a growth factor for a number of human cancer cell lines, including small-cell lung carcinoma (SCLC) , and has been detected in human breast and prostate cancer (Haveman et al., eds. Recent Results in Cancer Research - Peptide Hormones in Lung Cancer, Springer-Verlag, New York: 1986). A number of these cancers are known to secrete peptide hormones related to GRP or bombesin. Consequently, antagonists to bombesin have been proposed as agents for the treatment of these cancers. Cuttitta et al . demonstrated that a specific monoclonal antibody to bombesin inhibited in vivo the growth of a human small-cell lung cancer cell line xenografted to nude mice (Cuttitta et al. , Cancer Survey 4:707-727 (1985)). In 3T3 murine fibroblasts which are responsive to the mitotic effecr of bombesin, Zachary and Rozengurt observed that a substance P antagonist (Spantide) acted as a bombesin antagonist (Zachary et al., Proc. Natl. Acad. Sci . (USA), 82:7616-7620 (1985)). Heinz-Erian et al. replaced His at position 12 in bombesin with D-Phe and observed bombesin antagonist activity in dispersed acini from guinea pig pancreas (Heinz-Erian et al., Am. J. of Physiol. 252:G439-G442 (1987)). Rivier reported work directed toward restricting the conformational freedom of the bioactive C-terminal decapeptide of bombesin by incorporating intramolecular disulfide bridges; however, Rivier mentioned that, so far, bombesin analogs with this modification fail to exhibit any antagonist activity (Rivier et al. , "Competitive Antagonists of Peptide Hormones," in Abstracts of the International Symposium on Bombesin-Like Peptides in Health and Disease, Rome, Italy (October, 1987). Abbreviations (uncommon) : pGlu = (pyroglutamatic acid); Nle = H 2 N-CH-COOH (norleucine) (CH 2 ) 3 -CH 3 Pal = 3-pyridyl-alanine β-leu = β - homoleucine γ-leu = gamma - homoleucine D-Cpa = D-p-chlorophenylalanine HyPro = hydroxyproline Nal = naphthylaianine Sar = sarcosine Sta (statine) = (3S, 4S)-4-amino-3- ydroxy-6-methylheptanoic acid, and has the chemical structure: AHPPA = (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoic acid ACHPA = (3S, 4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid; R = right (D) configuration; S = left (L) configuration; racemate = equal mix of R and S 1-methyl-His; 3-methyl-His = methyl (CH 3 ) group on nitrogen at positions 1 or 3 of Histidine: Summary of the Invention A linear peptide (i.e., noncyclic) which is an analog of naturally occurring, biologically active amphibian bombesin or mammalian gastrin " releasing peptide (GRP) having an active site and a binding site responsible for the binding of the peptide to a receptor on a target cell, cleavage of a peptide bond in the active site of naturally occurring bombesin or GRP being unnecessary for in vivo biological activity, the analog having one of the following modifications: (a) a deletion of a residue within the .active site and a modification of a residue outside of the active site, or (b) a replacement of one or two residues within the active site wirh a synthetic amino acid. The analog is capable of acting as a competitive inhibitor of the naturally occurring peptide 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. The locations of the modifications that give rise to antagonists are determined by the location of the active site in the naturally occurring peptide. For example, the linear peptides for which introduction of a non-peptide bond between two residues, or the replacement of two natural amino acids with a synthetic β- or γ- amino acid, or the deletion ("des") of the C-terminal residue are useful in creating or enhancing antagonist activity are those in which activity is associated with the two C-terminal 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 one amino acid in the carboxy terminal half of the peptide, and the linear peptide of the invention includes that amino acid in its carboxy terminal half. Similarly, where the active site is located in the amino terminal portion of the naturally occurring peptide, the corresponding analogs of the invention will possess modifications in their amino terminal portions. In preferred embodiments, the active site includes at least one amino acid residue located in the carboxyl terminal half of the naturally occurring biologically active peptide and that amino acid residue is located in the carboxyl terminal half of the linear peptide. In other preferred embodiments, the active site includes at least one amino acid residue located in the amino terminal half of the naturally occurring biologically active peptide and that amino acid residue is located in the amino terminal half of the linear pep ide. Modifications can be introduced in a region involved in receptor binding, or in a non-binding region. Preferably, analogs of the invention are 25% homologous, most preferably, 50% homologous, with the naturally occurring peptides. The analogs of the invention may have one of the modifications given in the generic formulae given below; either a non-peptide bond instead of a peptide bond between an amino acid of the active site and an adjacent amino acid; or a statine or AHPPA or ACHPA residue, or a β- or γ- amino acid in place of one or two natural amino acids; or a deletion of the C-terminal amino acid which may or may not be accompanied by the addition of a substituent on the actual C-terminal group or the presence of an N-terminal residue that is not the natural N-terminal amino acid of the peptides from which the analogs are derived. (Statine, AHPPA, and ACHPA have the chemical structures defined above. Where statine is used herein, AHPPA or ACHPA may also be used.) 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 2 ~NH; or, less preferably, that the residue bonded to the carbon atom has a sulfur atom or a methylene carbon in place of its amino group, i.e., CH 2 -S or CO-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. ) One modification of the naturally occurring peptide to create an antagonist is of the amino terminal end of the molecule, which may be an electron-donating residue, e.g., a nitrogen-containing ' amino acid, such as 5 those described for the amino terminal positions in the generic formulae below; for example, the N-terminal ) amino acid, which is A or, if A is deleted, is 1 A1 or, if A0 and A1 are deleted, is A2 below, t may be an aromatic D-isomer, or may be an alkylated 10 amino acid. (Where "D" is not designated as the configuration of an amino acid, L is intended.) Anothe-r modification is of the C-terminal residue, which may be any of the "W" groups described below. The invention includes a therapeutic peptide 15 comprising between seven and nine amino acid residues, inclusive, the peptide being an analog of one of the following naturally occurring peptides terminating at the carboxy-terminus with a Met residue: (a) litorin; (b) neuromedin; (c) the ten amino acid carboxy-terminal 20 region of mammalian gastrin releasing peptide; and (d) the ten amino acid carboxy-terminal region of amphibian bombesin, the therapeutic peptide being of the formula: wherein _ A = Gly, Nle, α-aminobutyric acid, or the D-isomer of any of Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br, N0 2 , 30 OH, H or CH 3 ), Trp, Cys, or β-Nal, or is deleted; ~~~ "-~ A = the D- or L-isomer of any of pGlu, Nle, or α-aminobutyric acid, or the D-isomer of any of Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br, 0 2 , OH, H or CH- , Trp, Cys, or β-Nal, or is deleted; 2 A = pGlu, Gly, Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br, N0 2 , OH, H or CH 3 ), Trp, Cys, β-Nal, His, 1-methyl-His, or 3-methyl-His; A 4 = Ala, Val, Gin, Asn, Gly, Leu, He, Nle, α-aminobutyric acid, Met, p-X-Phe (where X = F, Cl, Br, 0 2 , OH, H or CH-), Trp, Cys, or A = Gin, Asn, Gly, Ala, Leu, He, Nle, α-aminobutyric acid, Met, Val, p-X-Phe (where X - F, Cl, Br, OH, H or CH 3 ), Trp, Thr, or β-Nal; A = Sar, Gly, or the D-isomer of any of Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br, N0 2 , OH, H or CH 3 ), Trp, Cys, or 7 A = 1-methyl-His, 3-methyl-His, or His; provided that if A is present, A cannot be pGlu; and if A 0 or A1 is present, A2 cannot be pGlu; and when A is deleted and A is pGlu, R 1 must be H and R 2 must be the portion of Glu that forms the imine ring in pGlu; and further provided that W can be: wherein Rd- is CHR,14,-(CK2, nl- (where R.1,4„ is either H or OH; and nl may be either of 1 or 0), or is deleted, and Z, is the identifying group of any one of the amino acids Gly, Ala, cyclohexyl-Ala, Val, Leu, He, Ser, Asp, Asn, Glu, Gin, p-X-Phe (where X = H, F, Cl, Br, N0 2 , OH, or CH 3 ), Trp, Cys, Met, Pro, HyPro, or isopropyl, cyclohexylmethyl, β-nal, β-napthylmethyl, or phenylmethyl; and V is either C 3 _ 20 alkinyl, phenyl, napthyl, or C 7 , Q phenylalkyl, and each R κ , and R,., independently, is any of H, C, 12 alkyl, C_ , 0 phenylalkyl, lower acyl, or /R.lo c where R 15 is any of H, C._ 12 alkyl, C ? _ 10 phenylalkyl, or lower acyl; provided that when one of R 5 or R g is NHR- 5 , the other is H; and provided that any asymmetric carbon atom can be R, S or a racemic mixture; and further provided that each R. and R 2 , independently, is H, C, ,, alkyl, C_ ,. phenylalkyl, COE ^ (where E^ is C 1 _ 2 Q alkyl, C 3 _ 2Q alkenyl, C 3-20 al ^i n y^' phenyl, naphthyl, or C__ 10 phenylalkyl), or lower acyl, and R, and R 2 are bonded to the N-terminal amino acid of the peptide, and further provided that when one of R., or R 2 is COE.^, the other must be H, or a pharmaceutically acceptable salt thereof. Preferably, the therapeutic peptide has the - formula wherein A = Gly, D-Phe, or is deleted; A = p-Glu, D-Phe, D-Ala, D-β-Nal, D-Cpa, or D-Asn; 2 A = Gin, His, 1-methyl-His, or 3-methyl-His; A 4 = Ala; A 5 = Val; = Sar, Gly, D-Phe, or D-Ala A 7 = His; provided that where R 3 is CH 2 -CH 2 , Z. is the identifying group of Leu or Phe; or where R 3 is CH 2 , Z χ is the identifying group of β-Leu or Leu; or where R 3 is CH0H-CH 2 , Z. is the identifying group of Leu or is isopropyl, cyclohexylmethyl, β-naphthylmethyl, or phenyl ethyl; provided that V is R_ N \ V and each R 5 and R g is H. Preferably, the peptide is of the generic formula wherein V is NHRδ C where R6- is NH2- . Most preferably the therapeutic peptide has the following amino acid formulas: pGlu-Gln-Trp-Ala-Val-Gly-His-statine-amide; and D-p-Cl-Phe-Gln-Trp-Ala-Val-Gly-His-β-Leu-NH 2 . The invention also includes a therapeutic peptide comprising between eight and ten amino acid residues, inclusive, the peptide being an analog of one of the following naturally occurring peptides terminating at the carboxy-terminus with a Met residue: (a) litorin; (b) neuromedin; (c) the ten amino acid carboxy-terminal region of mammalian gastrin releasing peptide; and (d) the ten amino acid carboxy-terminal region of amphibian bombesin, the therapeutic peptide being of the formula: wnerem A = Gly, Nle, α-aminobutyric acid, or the D-isomer of any of Ala, Vai, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br, 0 2 , OH, H or CH 3 ), Trp, Cys, cr β-Nal, or is deleted; A = the D- or L-isomer of any of pGlu, Nle, or α-aminobutyric acid, or the D-isomer of any of Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br, N0 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal, or is deleted; 2 A = pGlu, Gly, Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br, 0 2 , OH, H or CH 3 ), Trp, Cys, β-Nal, His, 1-methyl-His, or 3-methyl-His; 4 A = Ala, Val, Gin, Asn, Gly, Leu, He, Nle, α-aminobutyric acid. Met, p-X-Phe (where X = F, Cl, Br, N0 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal; 5 A = Gin, Asn, Gly, Ala, Leu, He, Nle, α-aminobutyric acid, Met, Val, p-X-Phe (where X = F, Cl, Br, OH, H or CH 3 ), Trp, Thr, or A = Sar, Gly, or the D-isomer of any of Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, • Cl, Br, N0 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal; 7 A = 1-methyl-His, 3-methyl-His, or His; provided that if A is present, A 1 cannot be pGlu; 0 1 2 and if A or A is present, A cannot be pGlu; and when A is deleted and A 1 is pGlu, R. must be H and R 2 must be the portion of Glu that forms the imine ring in pGlu; and further provided that W can be: wherein R 4 is CH 2 ~NH, CH 2 ~S, CO-CH 2 , or CH 2 -CH 2 , and each of Z., and Z 2 , independently, is the identifying group of any one of the amino acids Gly, Ala, Val, Leu, He, Ser, Asp, Asn, Glu, Gin, β-Nal, p-X-Phe (where X = H, F, Cl, Br, N0 2 , OH or CH 3 ), Trp, Cys, Met, Pro, HyPro, cyclohexyl-Ala, or cyclohexylmethyl; provided that where R. is CH 2 -NH and Z 2 is the identifying group of any one of the amino acids Gly, Ala, Val, Leu, He, Ser, Asp, Asn, Glu, Gin, p-X-Phe (where X = H, F, Cl, Br, N0 2 , OH or CH 3 ), Trp, Cys, Met, Pro, HyPro, or cyclohexylmethyl, Z^ can only be the identifying group of any one of the amino acids Ser, Asp, Glu, Cys, Pro, HyPro, or cylcohexylmethyl; and provided that where R. is CH 2 ~NH and Z. is the identifying group of any one of the amino acids Gly, Ala, Val, Leu, He, Ser, Asp, Asn, Glu, Gin, p-X-Phe (where X = H, F, Cl, Br, 0 2 , OH or CH 3 ), Trp, Cys, Met, Pro, or HyPro, Z 2 can only be the identifying group of any one of the amino acids Ser, Asp, Glu, Cys, Pro, HyPro, or cylcohexylmethyl; and V is and R_, independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl; and provided that any asymmetric carbon atom can be R, S or a racemic mixture; and further provided that each χ and R 2 , independently, is H, C l-12 alk ^ 1 ' C 7-ιo Phenylalkyl, C0E χ (where E χ is C 1 _ 20 alkyl, C 3 _ 20 alkenyl, C 3 _ 2Q alkinyl, phenyl, naphthyl, or C__ 10 phenylalkyl), or lower acyl, and R. and 2 are bonded to the N-terminai amino acid of the peptide, and further provided that when one of R. or R 2 is COE-, the other must be H, or a pharmaceutically acceptable salt thereof. Preferably, the therapeutic peptide has the formula wherein A = Gly, D-Phe, or is deleted; A = p-Glu, D-Phe, D-Ala, D-β-Nal, D-Cpa, or D-Asn; A 2 = Gin, His, 1-methyl-His, or 3-methyi-His; A 4 = Ala; A 5 = Val; A 6 = Sar, Gly, D-Phe, or D-Ala; ~ - ~ ~ " --^ ' A 7 = His; where R. is CH 2 ~NH, each Z., is cyclohexylmethyl or is the identifying group of Leu or Phe; or Z, is the identifying group of Met, Leu or Phe. Most preferably, the therapeutic peptide includes D-β-Nal at position A , where each of Z 1 and Z 2 , independently, is Leu or Phe. Examples of such peptides are: D-β-Nal Gln-Trp-Ala-Val-Gly-His-Leuψ[CH 2 NH]Leu-NH 2 , or D-β-Nal-Gln-Trp-Ala-Val-Gly-His-Leuψ[CH 2 NH]Phe-NH 2 . In additon, the therapeutic peptide may include where R 4 is CH 2 ~NH, and the carbon atom bonded to Z 2 is of the R configuration. An example of such a peptide is D-Phe-Gln-Trp-Ala-Val-Gly-His-Leuψ[CH,,NH]-D-Phe-NH . In addi .ti.on, the peptide may include where A0 or A is a D amino acid, V is OR,; for example, a methylester derivative such as the therapeutic peptide Dr-Phe-Gln-Trp-Ala-Va1-Gly-His-Leu-Met-methy1ester. The invention also includes a therapeutic peptide comprising between seven and nine aminα acid residues, inclusive, the peptide being an analog of one of the following naturally occurring peptides terminating at the carboxy-terminus with a Met residue: (a) litorin; (b) neuromedin; (c) the ten amino acid carboxy-terminal region of mammalian gastrin releasing peptide; and (d) the ten amino acid carboxy-terminal region of amphibian bombesin, the therapeutic peptide being of the formula: l A°-A 1 -A 2 -Trp-A' 1 - A 5 -A 6 -A 7 -W wherein A = Gly, Nle, α-aminobutyric acid, or the D-isomer of any of Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br, N0 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal, or is deleted; A = the D- or L-isomer of any of pGlu, Nle, or α-aminobutyriσ acid, or the D-isomer of any of Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br, N0 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal, or is deleted; 2 A = pGlu, Gly, Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br, N0 2 , OH, H or CH 3 ), Trp, Cys, β-Nal, His, 1-methyl-His, or 3-methyl-His; A = Ala, Val, Gin, Asn, Gly, Leu, He, Nle, α-aminobutyric acid, Met, p-X-Phe (where X = F, Cl, Br, N0 2 , OH, H or CH 3 ) , Trp, Cys, or β-Nal; A = Gin, Asn, Gly, Ala, Leu, He, Nle, α-aminobutyric acid, Met, Val, p-X-Phe (where X = F, Cl, Br, OH, H or CH 3 ), Trp, Thr, or β-Nal; A = Sar, Gly, or the D-iscmer of any of Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br, N0 2 , OH, H or CH 3 ), Trp, Cys, or A = 1-methyl-His, 3-methyl-His, or His; provided that if A is present, A cannot be pGlu; and if A 0 or A1 is"present, A2 cannot be pGlu; ana when A is deleted and A is pGlu, R. must be H and R 2 must be the portion of Glu that forms the imine ring in pGlu; and further provided that W can be: wherein Z. is the identifying group of any one of the amino acids Gly, Ala, Val, Leu, He, Ser, Asp, Asn, Glu, Gin, p-X-Phe (where X - H, F, Cl, Br, N0 2 , OH or CH 3 ), Trp, Cys, Met, Pro, or HyPro; and each R g , R 1Q , and R η i. independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl; and provided that any asymmetric carbon atom can be R, S or a racemic mixture; and further provided that each R. and R 2 , independently, is H, C 1 _ 12 alkyl, C__ 1Q phenylalkyl, COE- j^ (where E^ ^ is C-_ 20 alkyl, C 3 _ 2Q alkenyl, C 3-20 ^fc^y 1 ' Phenyl, naphthyl, or C_ , Q phenylalkyl), or lower acyl, and R. and R 2 are bonded to the N-terminal amino acid of the peptide, and further provided that when one of R. or R_ is COE,, the other must be K, or a pharmaceutically acceptable salt thereof. Preferably, the peptide includes wherein A = Gly, D-Phe, or is deleted; A = p-Glu, D-Phe, D-Ala, D-β-Nal, D-Cpa, or D-Asn; 2 A = Gin, His, 1-methyl-His, or 3-methyl-His; A 4 = Ala; A 5 = Val; A = Sar, Gly, D-Phe, or D-Ala; A 7 = His; provided that Z., is the identifying group of any one of the amino acids Leu or D or L p-X-Phe (where X = H, ' F, Cl, Br, N0 2 , OH or CH 3 ); and each R g , R 1Q and R.,, independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl. Most preferably, the peptide includes wherein Z 1 is Leu, R„ is H, and each R 1Q and R,, is lower alkyl. Examples of such a peptide are: D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-ethylamide; or D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NH 2 . The inventional also includes a therapeutic peptide comprising between six and eight amino acid residues, inclusive, the peptide being an analog of one of the following naturally occurring peptides terminating at the carboxy-terminus with a Met residue: (a) litorin; (b) neuromedin; (c) the ten amino acid carboxy-terminal region of mammalian gastrin releasing peptide; and (d) the ten amino acid carboxy-terminal region of amphibian bombesin, the therapeutic peptide being of the formula: wnerem A = Gly, Nle, α-aminobutyric acid, or the D-isomer of any of Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br , 0 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal, or is deleted; A = -the D- or L-isomer of any of pGlu, Nle, or α-aminobutyriσ acid, or the D-isomer of any of Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br, N0 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal, or is deleted; 2 A = pGlu, Gly, Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br, N0 2 , OH, H or CH 3 ), Trp, Cys, β-Nal, His, 1-methyl-His, or 3-methyl-His; A 4 = Ala, Val, Gin, Asn, Gly, Leu, He, Nle, α-aminobutyric acid, Met, p-X-Phe (where X = F, Cl, Br, N0 2 , OH, H or CH 3 ), Trp, Cys, or A 3 = Gin, Asn, Gly, Ala, Leu, He, Nle, α-aminobutyric acid, Met, Val, p-X-Phe (where X = F, Cl, Br, OH, H or CH 3 ), Trp, Thr, or A = Sar, Gly, or the D-isomer of any of Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br, 0 2 , OH, H or CH 3 , Trp, Cys, or A l-His, 3-methyl-His, or His; provided that if is present, A cannot be pGlu; 0 1 2 and if A or A is present, A cannot be pGlu; and 0 1 when A is deleted and A is pGlu, R. must be H and R 2 must be the portion of Glu that forms the imine ring in pGlu; and further provided that W can be: / R 12 -N R 13 wherein each R. and R,,, independently, is H, lower alkyl, lower phenylalkyl, or lower naphtnylalkyl; provided that any asymmetric carbon atom can be R, S or a racemic mixture; and further provided that each R χ and R 2 , independently, is H, C\ 12 alkyl, C 7 _ 10 phenylalkyl, COΞ., (where E χ is C,_ 20 alkyl, C 3 - 20 a l^en l, C 3 _ 20 a l^inyl, phenyl, naphthyl, or C 7 - 10 P nen y^ a ^ c l ) ' or lower acyl, and R , and R 2 are bonded to the N-terminal amino acid of the peptide, and further provided that when one of R, or 2 is COE the other must be H, or a pharmaceutically acceptable salt thereof. Preferably, the therapeutic peptide includes wherein A = Gly, D-Phe, or is deleted; A = p-Glu, D-Phe, D-Ala, D-β-Nal, D-Cpa, or D-Asn; 2 A = Gin, His, 1-methyl-His, or 3-methyl-His; A 4 = Ala; A 5 - Val; ,6 = Sar, Gly, D-Phe, or D-Ala; ,7 - His; where each R 12 and R 13 , is H; and each R, and R 2 , independently, is H, lower alkyl, or lower acyl. Preferably, where either of N 12 or N- 3 is other than H, A 7 is His, A 6 is Gly, A 5 is Val, A 4 i■s Ala, and A2 is His; and where either of R, or R 2 is other than H, A 1 must not be deleted. The invention also includes a bombesin therapeutic peptide of the formula: pGlu-Gln-Arg-Leu-Gly-Asn-Gin-Trp-Ala-Val-Gly-His- Statine. The invention also includes an effective bombesin antagonistic peptide containing the amino acid formula: V-A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -A 10 - R 2 wherein A = pGlu, D or L, or is deleted; 2 A = Gin, Asn, Gly, Ala, Leu, He, Nle, α-aminobutyriσ acid, Met, Val, Phe, p-X-Phe (X = F, Cl, 3r, OH or CH 3 ), Trp, β-naphthylalanine or is deleted; 3 A = Arg, D-Arg, Lys, D-Lys or is deleted; 4 A = Gin, Asn, Gly, Ala, Leu, He, Nle, α-aminobutyric acid, Met, Val, Phe, p-X-Phe (X = F, Cl, Br, OH or CH 3 >, Trp, β-naphthylalanine or is deleted ; A = Gin, Asn, Gly, Ala, Leu, He, Nle, α-aminobutyriσ acid. Met, Val, Phe, D-Phe, p-X-Phe (X = F, Cl, Br, OH or CH 3 ), Trp, β-naphthylalanine, D-Ala or is deleted; A = Gin, Asn, Gly, Ala, D-Ala, N-Ac-D-Ala, Leu, He, Nle, α-aminobutyric acid, Met, Val, Phe, p-X-Phe (X = F, Cl, Br, OH or CH 3 ), Trp, p-Glu, β-naphthylalanine or is deleted; 7 A = Gin, Asn, Gly, Ala, Leu, He, Nle, α-aminobutyric acid, Met, Val, Phe, D-Phe, p-X-Phe (X = F, Cl, Br, OH or CH 3 ), Trp, Lys, His, or β-naphthylalanine; A = Trp or Met; 9 A = Gin, Asn, Gly, Ala, Leu, He, Nle, α-aminobutyric acid, Met, Val, Phe, p-X-Phe (X = F, Cl, Br, OH or CH- , Trp, or β-naphthyl lanine, D or L; A 10 = Gin, Asn, Gly, Ala, Leu, He, Nle, α-aminobutyric acid, Met, Val, Phe, p-X-Phe (X = F, Cl, Br, OH or CH 3 ), Trp, Thr, or β-naphthylalanine; A 11 = Gly, Phe, D or L; A 12 - His, Phe, or p-X-Phe (X = F, Cl, Br, OH, CH,) , D or L; A 13 = Gin, Asn, Gly, Ala, Leu, He, Nle, α-aminobutyric acid, Met, Val, Phe, p-X-Phe (X = F, Cl, Br, OH or CH 3 ), Trp, or β-naphthylalanine; 14 A = Gin, Asn, Gly, Ala, Leu, He, Nle, α-aminobutyric acid, Met, Val, Phe, p-X-Phe (X = F, Cl, Br, OH or CH.-), Trp, or β-naphthy1a1anine; provided that each R χ , R 2 , R 3 , and R 4 , independently, is H, C 1-12 alkyl, C__ 1Q phenylalkyl, COE. (where Ε* 1 is C 1 _ 2Q alkyl, C 3 _ 2fJ alkenyl, C 3 _ 2Q alkinyl , phenyl, naphthyl, or C 7 _ 1Q phenylalkyl), or COOE 2 (where Ξ 2 is C, , 0 alkyl or C 7 _ 10 phenylalkyl), and R, and , are bonded to the N-terminal amino acid of the peptide, which can be A 1, A , A3, A 4, A5, A6 , or A7, and further provided that when one of R 1 or R 2 is COE. or COOE 2 , the other must be H, and when one of R3, or R4. is C0E n l or COOE,, the other must be H, and further provided that when A 1 = pGlu, R. must be H and R 2 must be the portion of Glu that forms the imine ring in pGlu; and for each of the residues A , A , A , A , A 13 . . . and A , independently, the carbon atom participating in the amide bond between that residue and the nitrogen atom of the alpha amino group of the adjacent amino acid residue may be a carbonyl carbon or may be reduced to a methylene carbon, provided that at least one such carbon atom must be reduced to a methylene carbon, where the peptide further comprises A 5 = Cys; A = Cys or a D-isomer of any of the amino acids described for this position; 7 A = pGlu, Cys, 1-methyl-His, or 3-methyl-His; A 9 = Cys; A = Sar, or the D-isomer of any of Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH_), Trp, Cys, or β-Nal; 12 A = 1-methyl-His, or 3-methyl-His; and where A 14 may be deleted. Most preferably, this therapeutic peptide is of the formula: D-p-Cl-Phe-Gln-Trp-Ala-Val-Gly-His-Leuψ[CH 2 NH]Phe-NH 2 Preferably, the amino acid sequence of the therapeutic peptides of the formulas described herein are at least 25% homologous with the amino acid sequence of the naturally occurring peptide; most preferably, this homology is at least 50%. (Non-peptide bonds in which the peptide bond is reduced are symbolized herein by "ψ[CH 2 NH3" or ".) Antagonists of the invention are useful for treating diseases involving the malignant or benign proliferation of tissue, such as all forms of cancer where bombesin-related or GRP-related substances act as autocrine or paraσrine mitotic factors, e.g., cancers of the gastrointestinal tract, pancreatic cancer, colon cancer, lung cancer, particularly the small cell subtype, or breast cancer; or for treating artherosclerosis, and disorders of gastrointestinal tissues related to gastric and pancreatic secretions and motility; for example, for causing the suppression of amylase secretion, or for appetite control. In the generic formulae given above, when any one of R.-R 13 „or R.g. is an aromatic?- li ophilic 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 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 3 , the identifying group of valine is (CH 3 ) 2 CH, the identifying group of lysine is H 3 N + (CH 2 ) 4 and the identifying group of phenylalanine is (C g H 6 )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 α, β, or γ. 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 graph of tumor growth curves for NCI-H69 xenografts. Fig. 2 is a series of amino acid sequences of naturally occurring peptides of which peptides of the invention are analogs. Fig. 3 is a graph showing the effect of injection of the bombesin analog D-Phe BN(6-13/methylester on bombesin-stimuiated pancreatic amylase assay. We now describe the structure, synthesis, and use of the preferred embodiments of the invention. Structure The peptides of the invention all have a non-peptide bond in at least one of the indicated positions, except for the statine substituted analogs and β-leu, such as sta 8 -desLeu 8 -Met 9 litorin. 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. 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. Any one of the amino acids in positions 0, l, 2, and 9 of the litorin antagonists may be deleted from the peptides, and the peptides are still active as antagonists. The peptides of the invention can be provided in the form of pharmaceutically acceptable salts. Examples of preferred salts are those with therapeutiσally 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 carboxyrr.ethyl cellulose, and salts with inorganic acids such as the hydrohalic acids, e.g., hydrochloric acid, sulfuric acid, or phosphoric acid. Synthesis of Litorin Analogs The synthesis of the litorin antagonist pGlu-Gln-Trp-Ala-Val-Gly-His-Leuψ[CH 2 NH]Leu-NH 2 follows. Other antagonists of bombesin, litorin, neuro edin, or GRP can be prepared by making appropriate modifications of the following synthetic method. The first step is the preparation of the intermediate pGlu-Gln-Trp-Ala-Va1-Gly-His(benzyloxycarbony1)-Leuψ[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) cf sodium cyanoborohydride (Sasaki and Coy, Peptides 8:119-121 (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-His(benzyloxycarbonyl) , Boc-Gly, Boc-Val, Boc-Ala, Boc-Trp, Boc-Gln (coupled as a 6 M excess of the p-nitrophenylester) , and pGlu. 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 eluted on a column (2.5 x 100 mm) of Sephadex G-25 (Pharmacia Fine Chemicals, Inc.). Fractions containing a major component by uv absorption and thin layer chromatography (TLC) are then pooled, evaporated to a small volume and applied to a column (2.5 x 50 cm) of octadecylsilane-silica (Whatman LRP-1, 15-20 μm mesh size) . The peptide is eluted with a linear gradient of 0-30% acetonitrile in 0.1% trifluoroacetic acid in water. Fractions are examined by TLC and analytical high performance liquid chromatography (HPLC) and pooled to give maximum purity. Repeated lyophilization of the solution from water gives 60 mg of the product as a white, fluffy powder. The product is found to be homogeneous by HPLC and TLC. Amino acid analysis of an acid hydrolysate confirms the composition of the peptide. The presence of the Leuψ[CH 2 ~NH]Leu bond is demonstrated by fast atom bombardment mass spectrometry. pGlu-Gln-Trp-Ala-Val-Gly-His-Pheψ[CH 2 NH]Leu-NH 2 and pGlu-Gln-Trp-Ala-Val-Gly-His-Leuψ[CH 2 H]Leu-NH 2 or other peptides are prepared in similar yields in an analogous fashion by appropriately modifying the above procedure. Solid phase synthesis of D-Phe , Leu 8 ψ[CH 2 NH]D-Phe 9 -litorin, D-Phe-Gln-Trp-Ala- Val-Gly- His-Leuψ[CH 2 NH]-D-Phe-NH 2 , was carried out as follows: Boc-D-Phe-Gln-Trp-Ala-Val-Gly-His(tosyl)-Leuψ[CH 2 NH]- D-Phe-benzhydrylamine resin was synthesized first. Benzhydrylamine-polystyrene resin (Advanced Che Tech, Inc.) (1.25 g, 0.5 mmole) in the chloride ion form is placed in the reaction vessel of an Advanced ChemTech ACT 200 peptide synthesizer programmed to perform the reaction cycle described as steps (a) through (f) above. The neutralized resin is stirred with Boc-D-phenylalanine and diisopropylcarbodiimide (1.5 mmole each) in methylene chloride for 1 h and the resulting amino acid resin is then cycled through steps (a> to (g) in the above wash program. The Boc group is then removed by TFA treatment. Boc-leucine aldehyde (1.25 mmoles), prepared by the method of Fehrentz and Castro (1), is dissolved in 5 ml of dry DMF and added to the resin TFA salt suspension followed by the addition of 100 mg (2 mmoles) of sodium cyanoborohydride (2,3). After stirring for 1 h, the resin mixure 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 by the same procedure: Boc-His(benzyloxycarbonyl) , Boc-Gly, Boc-Val, Boc-Ala, Boc-Trp, Boc-Gln (coupled in the presence of 1 equiv. hydroxybenzotriazole), Boc-D-Phe (coupled in the presence of 1 equiv. hydroxybenzotriazole). After drying, the peptide resin weighed 1.93 g. The resin (1.93 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 precipitated and washed with ether. The crude peptide is dissolved in a minimum volume of 2 M acetic acid and eluted on a column (2.5 x 100 mm) of Sephadex G-25. Fractions containing a major component by uv absorption and thin layer chromatography are then pooled, evaporated to a small volume and applied to a column (2.5 x 50 cm) of Vydac octadecylsilane (10-15 uM) . This is eluted with a linear gradient of 15-45% acetonitrile in 0.1% trifluoroacetic acid in water. Fractions are examined by thin layer chromatography and analytical high performance liquid chromatography and pooled to give maximum purity. Repeated lyophlization of the solution from water gives 120 mg of the product as a white, fluffy powder. Other peptides, e.g., D-p-Cl-Phe-Gln-Trp-Ala- Val-Gly-His-Leuψ_CH 2 NH]-D-Phe-NH 2 , may be synthesized using essential the same procedure. Synthesis of Leu8ψ[CH,NH] D-Phe9 Litorin Solid phase synthesis of D-Phe-Gln-Trp-Ala-Val-Gly-His-Leuψ[CH 2 NH]-D-Phe-NH 2 was carried out as follows: Boc-D-Phe-Gln-Trp-Ala-Val-Gly-His(tosyl)-Leuψ[CH 2 NH]- D-Phe-benzhydrylamine resin was synthesized first. Benzhydrylamine-polystyrene resin (Advanced ChemTech, Inc.) (1.25 g, 0.5 mmole) in the chloride ion form is placed in the reaction vessel of an Advanced ChemTech ACT 200 peptide synthesizer programmed to perform the following reaction cycle: (a) methylene chloride; (b) 33% trifluoroacetic acid in methylene chloride (2 times for 1 and 25 min each); (c) methylene chloride; (d) ethanol; (e) methylene chloride; (f) 10% triethylamine in chloroform. The neutralized resin is stirred with Boσ-D-phenylalanine and diisopropylcarbodiimide (1.5 mmole each) in methylene chloride for 1 h and the resulting amino acid resin is then cycled through steps (a) to (g) in the above wash program. The Boc group is then removed by TFA treatment. Boc-leucine aldehyde (1.25 mmoles), prepared by the method of Fehrentz and Castro (1), is dissolved in 5 ml of dry DMF and added to the resin TFA salt suspension followed by the addition of 100 mg (2 mmoles) of sodium cyanoborohydride (2,3). After stirring for 1 h, the resin mixure 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 by the same procedure: Boc-His(benzyloxycarbonyl) , Boc-Gly, Boc-Val, Boc-Ala, Boc-Trp, Boc-Gln (coupled in the presence of 1 equiv. hydroxybenzot iazole), Boc-D-Phe (coupled in the presence of 1 equiv. hydroxybenzotriazole). After drying, the peptide resin weighed 1.93 g. The resin (1.93 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 precipitated and washed with ether. The crude peptide is dissolved in a minimum volume of 2 M cjbetic acid and eluted on a column (2.5 x 100 mm) of Sephadex G-25. Fractions containing a major component bj uv absorption and thin layer chromatography are then pooled, evaporated to a small volume and applied to a column (2.5 x 50 cm) ' of Vydac octadecylsilane (10-15 uM) . This is eluted with a linear gradient of 15-45% acetonitrile in 0.1% trifluoroacetic acid in water. Fractions are examined by thin layer chromatography and analytical high performance liquid chromatography and pooled to give maximum purity. Repeated lyophlization of the solution from water gives 120 mg of the product as a white, fluffy powder. The product is found to be homogeneous by hplc and tic. Amino acid analysis of an acid hydrolysate confirms the composition of the octapeptide. The presence of the Leuψ.O TH] peptide bond is demonstrated by fast atom bombardment mass spectrometry. Synthesis of D-Phe -Des-Met Litorin Solid phase synthesis of D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NH 2 was carried out as follows. — Step (1): Benzhydrylamine-polystyrene resin (Advanced ChemTech, Inc. (0.62 gm, 0.25 mmole) in the chloride ion form is placed in the reacton vessel of an ACT 200 peptide synthesizer programmed to perform the following reaction cycle: (a) methylene chloride; (b) 33% trifluoroacetic acid in methylene chloride (2 times for 1 and 25 min each); (c) methylene chloride; (d) ethanol; (e) methylene chloride; (f) 10% triethylamine in chloroform. The neutralized resin is stirred with Boc-leucine and diisopropylcarbodiimide (1.5 mmole each) in methylene chloride for 1 hr and the resulting amino acid resin is then cycled through steps (a) to (g) in the above wash program. The following amino acids (1.5 mmole) are then coupled successively by the same procedure: Boc-His (benzyloxycarbonyl, Boc-Gly, Boc-Val, Boc-Ala, Boc-Trp, Boc-Gln (coupled as a 6M excess of the p-nitrophenylester, and pGlu (coupled in the presence of hydroxzybenzotriazole) . After drying, the peptide resin weighed 0.92 g. Step (2): The resin (0.92 g) is then mixed with anisole (5 ml), dithiothreitol (200 mg) 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 precipitated and washed with ether. The crude peptide is dissolved in a minimum volume of 2 M acetic acid and eluted on a column (2.5 x 100 cm) of Sephadex G-25. Fractions containing a major component by UV absorption and thin layer chromatography are then pooled, evaporated to a small volume and applied to a column (2.5 x 50 cm) of Vydac octadecylsilane (10-15 microM) . The column is eluted with a linear gradient of 0-30% acetonitrile in 0.1% trifluoroacetic acid in water. Fractions are examined by thin layer chromatography and pooled to give maximum purity. Repeated lyophilization of the solution from water gives a white, fluffy powder; this product is found to be homogeneous by hplc and tic. Amino acid analysis of an acid hydrolysate confirms the compositon of the peptide. Synthesis of D-Nal-Gln-Trp-Ala-Val-Gly-His-Leu-NH 2 was accomplished using the same procedure as described above (0.62 g, 0.25 mmole of benzyhycrylamine resin in step (1), and 0.92 g in step (2)). Synthesis of N-acetyl-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NH 2 was accomplished using the same procedure as that described above, using 0.62 g (0.25 mmole) of benzhydrylamine resin in step (1), and mixing 0.92 g of the resin with anisole in step(2), except that the final Boc group was removed and the resin acetylated with acetic anhydride in methylene chloride. 8 9 Synthesis of Sta -Des-Met Litorin A statine, AHPPA, or ACHPA residue can be substituted in place of any two amino acids of the peptide, where the peptide contains only peptide bonds. For example, sta 8-des Met9 litorin was prepared in an analagous fashion by first coupling statine to the resin and then proceeding with the addition of Boc-His(benzylocarbonyl) . Statine or Boc-statine can be synthesized according to the method of Rich et al. , 1978, J. Organic Chem. 43; 3624; and Rich et al. , 1980, J. Med. Chem. 23: 27, and AHPPA and ACHPA can be synthesized according to the method of Hui et al., 1987, J. Med. Chem. 30.: 1287; Schuda et al., 1988, J. Org. Chem. 53:873; and Rich et al., 1988, J. Org. Chem. 53:869. Solid-phase synthesis of the peptide BIM-26120, pGlu-Gln-Trp-Ala-Val-Gly-His-Sta-NH 2 , was accomplished through the use of the following procedures in which alpha-t-butoxycarbonyl statine (prepared by the procedure of Rich et al., J. Org. Chem. 1978, 43, 3624) is first coupled to methylbenzhydrylamine-polystyrene resin. After acetylation, the intermediate p-Glu-Gln-Gln-Trp-Ala-Val-Gly-His(benzyloxycarbonyl)-Sta- methylbenzhydrylamine resin is prepared. The synthetic procedure used for this preparation follows in detail: 1. Incorporation of alpha-t-butoxycarbonyl statine on methylbenzhydrylamine resin. Methylbenzhydrylamine-polystyrene resin (Vega Biochemicals, Inc.) (1.0 g, 0.73 mmol) in the chloride ion form is placed in the reaction vessel of a Vega 250C Coupler peptide synthesizer. The synthesizer was programmed to perform the following reactions: (a) methylene chloride; (b) 10% triethylamine in chloroform; (c) methylene chloride; and (d) dimethylformamide. The neutralized resin is mixed for 18 hours with the preformed active ester made from alpha-t-butoxycarbonyl statine (1.46 mmol), diisopropyl carbodiimide (2 mmol), and hydroxybenzotriazole hydrate (1.46 mmol in dimethylformamide at 0° C. for one hour. The resulting amino acid resin is washed on the synthesizer with dimethylformamide and then methylene chloride. The resin mixture at this point was found by the Kaiser ninhydrin test (5 minutes) to have an 84% level of statine incorporation on the resin. Acetylation was performed by mixing the amino-acid resin for 15 minutes with N-acetyl imidazole (5 mmol) in methylene chloride. Derivatization to the 94-99% level of the free amino groups of the resin was indicated by the Kaiser ninhydrin test (5 minutes). The Boc-statine-resin is then washed with methylene chloride, 2. Couplings of the Remaining Amino Acids. The peptide synthesizer is programmed to perform the following reaction cycle: (a) methylene chloride; (b) 33% trifluoroacetic acid (TFA) in methylene chloride (2 times for 5 and 25 min. each); (c) methylene chloride; (d) isopropyl alcohol; (e) 10% triethylamine in chloroform; and (f) methylene chloride. The following amino acids (2.19 mmol) are then coupled successively by iisopropyl carbodiimide (4 mmol) alone or diisopropyl carbodiimide (4 mmol) plus hydroxybenzotriazole hydrate (1.47 or 0.73 mmol) and the resulting peptide-resin is washed on the synthesizer with dimethylformamide and then methylene chloride, and then cycled through the washing and deblocking steps (a) to (f) in the procedure described above. Boc-His (benzyloxycarbony1) (coupled in the presence of 2 equivalents hydroxybenzotriazole); Boc-Gly; Boc-Val; Boc-Ala and Boc-Trp (coupled as the pr.eforn.ed hydroxybenzotriazole active esters made by reaction at 0° C for one hour with 1 equivalent hydroxybenzotriazole hydrate); Boc-Gln and pGlu (also coupled as the preformed active esters of hydroxybenzotriazole made by reaction at 0° C for one hour with 1 equivalent hydroxybenzotriazole hydrate) . The completed peptide-resin is then washed with methanol and air dried. The peptide-resin described above (1.60 g, 0.73 mmol) is mixed with anisole (2.5 mL), dithioerythreitol (50 mg), and anhydrous hydrogen fluoride (30 mL) at 0° c. for one hour. • Excess hydrogen fluoride is evaporated rapidly under a stream of dry nitrogen, and the free peptide is precipitated and washed with ether. The crude peptide is dissolved in 100 mL of 1 M acetic acid and the solution is then evaporated under reduced pressure. The crude peptide is dissolved in a minimum volume of methanol/water 1/1 and triturated with 10 volumes of ethyl acetate. The triturated peptide is applied to a column (9.4 mm I.D. x 50 cm) of octadecvlsilane-silica (Whatman Partisil 10 ODS-2 M 9). The peptide is eluted with a linear gradient of 20-80% of 20/80 0.1% trifluoroacetic acid/acetonitrile in 0.1% trifluoroacetic acid in water. Fractions are examined by TLC and analytical high performance liquid chromatography (HPLC) and pooled to give maximum purity. Lyophilization of the solution from water gives 77 mg of the product as a white fluffy powder . Other compounds including D-Cpa 1, β-leu8, q desMet Litorin can be prepared as above and tested for effectiveness as agonists or antagonists in the following test program. Phase 1 - 3T3 Peotide Stimulated 1 Hj_ Thymidine Upt ke Assay Cell Culture. Stock cultures of Swiss 3T3 cells are grown in Dulbecco's Modified Eagles Medium (DMEM) supplemented with 10% fetal calf serum in humidified atmosphere of 10.% CO 2 /90% air at 37°C. For experimental use, the cells are seeded into 24-well cluster trays and used four days after the last change of medium. The cells are arrested in the G1/G0 phase of the cell cycle by changing to serum-free DMEM 24 hours prior to the thymidine uptake assay. Assay of DNA Synthesis. The cells are washed twice with 1ml aliquots of DMEM (-serum) then incubated with DMEM (-serum), 0.5μM [methyl- 3 H] thymidine (20Ci/mmole, New England Nuclear); bombesin (3nM), and initially four concentrations of the test compounds (1, 10, 100, lOOOnM) in a final volume of 1.0 ml. After 28 3 hours at 37°C [methyl- H] -thymidine incorporation into acid-insoluble pools is assayed as follows. The cells are washed twice with ice-cold 0.9% NaCl (1ml aliquots), and acid soluble radioactivity is removed by a 30 min. (4°C) incubation with 5% trichloroacetic acid (TCA). The cultures are then washed once (1ml) with 95% ethanol and solubilized by a 30 min. incubation (1ml) with 0. IN NaOH. The solubilized material is transferred to vials containing 10ml ScintA (Packard), and the radioactivity is determined by liquid scintillation spectrometry. Phase 2 - Small Cell Carcinoma (SCLC) - Bombesin 3 Stimulated H Thymidine Uptake Assay Cell Culture■ Cultures of the human cell carcinoma cell line (NCI-H69) (obtained from the American Type Culture Association) are maintained in RPMI 1640 medium supplemented with 10% fetal calf serum in 10% CO 2 /90% air at 37°C. Twenty-four hours prior to assay, the cells are washed with serura-free medium-- "" * ■ and seeded in 24-well cluster trays. Assay of DNA Synthesis■ Bombesin (InM), 3 0.5μM [methyl- H] thymidine (20 Ci/mmole, New England Nuclear), and four concentrations of the test compounds (1, 10, 100, lOOOnM) are added to the cultures to achieve a final volume of 0.5 ml. After a 28 hr incubation at 37°C, the cells are collected onto GF/B glass fiber filters, and the DNA is precipitated with ice-cold TCA. [ H] thymidine incorporation into acid-insoluble fractions of DNA is determined by liquid scintillation spectrometry. Phase 3 - Peptide-Induced Pancreatitis Male, Sprague- awley rats (250g) are used for these experiments. The test compound, or 0.9% NaCl is administered s.c. 15 min. prior to the bombesin injection. Bombesin injections are given s.c. at a dose of 10 μg/kg, and blood samples are obtained at 1 hr.30 min., 3hr. and 6hr. Plasma amylase concentration are determined by the Pantrak Amylase test. Phase 4- In Vitro Inhibition of [ I] Gastrin Releasing Peptide (GRP) Binding to Bombesin Receptors Membranes from various tissues (rat brain, rat pancreas, rat anterior pituitary, SCLC, 3T3 cells) are prepared by ho ogenization in 50mM TrisHCl containing 0.1% bovine serum albumin and 0.lmg/ml bacitracin followed by two centrifugations (39,000xgxl5 min., 4°C) with an intermediate resuspension in fresh buffer. For assay, aliquots (0.8ml) are incubated with 0.5nM 125 [ IJGRP ('2000 Ci/mmoi, A ersham Corp.) and various concentrations of the test compounds in a final volume of 0.5ml. After a 30 minute incubation at 4°C, the binding reaction is terminated by rapid filtration through Whatman GF/C filters that have been pre-soaked in 0.3% aqueous polethyleneimine to reduce the level of nonspecific binding. The filters and tubes are washed three times with 4ml aliquots of ice-cold buffer, and the radioactivity trapped on the filters is counted by gamma-spectrometry. Specific binding is defined as the total [ 125I]GRP bound minus that bound in the presence of lOOOnM bombesin. Phase 5- Inhibition of Gastrin Release The stomachs of anesthetized rats are perfused with saline collected over 15 minute periods via pyloric cannulation while the test peptide is infused through the femoral vein for periods between 0 and 150 minutes. Phase 6- In Vivo Antitumor Activity NCI-H69 small cell lung carcinoma cells were transplanted from in vitro culture by implanting each animal with the equivalent of 5 confluent 75 cm 2 tissue culture flasks in the right flank, ^n vitro NCI-H69 cells grow as a suspension ' of cellular aggregates. Therefore, no attempt was made to disaggregate the cell agglomerates by physical or chemical means. Tumor size was calculated as the average of two diameters, i.e., (length and width/2) mm. Results of Assays of Test Peptides A number of analogs of bombesin or GRP, each containing a non-peptide bond or a statine, AHPPA, or ACHPA residue, can be synthesized and tested in one or more of the above-described Phase 1 - 6 assays; the results of Phase 1 and 2 tests are given in Table 1 attached hereto. Table I shows formulas for the non-peptide analogues and results of in vitro inhibition 125 of [ I]GRP binding to 3T3 fibroblast bombesin receptors, and bombesin-stimulated [ H]Thymidine uptake by cultured 3T3 cells. (3T3 GRP receptor and thymidine uptake data are expressed in IC50 (nM) . ) Table 1 also gives results for non-peptide bond-containing analogs of one other naturally-occurring peptide, Neuromedin C, whose C-terminal seven amino acids are similar to those of bombesin and GRP. (In Table I, "Litorin" indicates a 9 residue peptide analog or its derivative, whereas "Neuromedin C" indicates a 10 residue analog or its derivative.) In Table I, the position of the non-peptide bond is indicated by the position of the symbol ψ[CH 2 NH]; i.e., ψ[CH 2 NH] is always shown preceding the amino acid " which, in that peptide, is bonded to the amino acid N-terminal to it via the non-peptide bond. Where no amino acid is specified under "structure", the non-peptide bond links the two peptides represented by the numbers given as post-scripts. In Table I, it can be seen that a preferred placement of the non-peptide bond in litorin analogs is at the A8 - A9 position; two of the most active analogs (as indicated by a low GRP receptor IC50 value) are BIM-26100 (Phe 8 ψ[CH 2 NH]Leu 9 ) and BIM-26101 (Leu 8 ψ[CH 2 NH]Leu 9 ). 5 In addition, as shown in Table I, BIM-26113 (D-Phe 1 , Leu 8 ψ[CH 2 NH]Leu 9 ) and BIM-26114 ) (D-Nal 1 , Leu 8 ψ[CH 2 NH]Leu 9 ) are active in the 3T3 GRP receptor binding and thymidine uptake assays. ! Most notably, BIM-26136 (D-Nal 1 , 8 9 10 Leu ψ[CH 2 NH]Phe ), which contains amino and carboxy terminal aromatic residues that are capable of forming a hydrophobic interaction, is the most potent analog. Finally, when statine or β-leucine replaces the 8 9 A and A residues of litorin, the resultant analogs 15 BIM-26120 and BIM-26182 are also potent antagonists. Table I also shows that Neuromedin C analogs . . . 9 containing a non-peptide bond between residues A - A 10 , e.g., BIM-26092, 26095, 26106, and 26107, are antagonists when tested in the 3T3 GRP receptor and 20 thymidine uptake assays. Table 1 also gives negative results for analogs of Neuromedin C, e.g., BIM-26108. Thus the non-peptide bond placement guidelines given herein should be used in conjunction with the routine assays described above to 25 select useful antagonists. Bombesin and Bombesin analogs have been shown to inhibit the effect of interleukin-2 (IL-2) (Fink et al., 1988, Klin. Wochenschr. 66, Suppl. 13, 273). Since • ' - IL-2 causes T lymphocytes to proliferate, it is possible 30 that litorin antagonists may prevent the inhibitory effect of Bombesin or its analogs on IL-2. IL-2 stimulated lymphocytes are capable of effectively lysing small cell lung carcinoma cells in vitro. Although Bombesin antagonists have a direct antiproliferative effect on neoplastic tissues, they may also favor proliferation of lymphocytes having lytic activity for small cell lung carcinoma. These observations prompted us to evaluate the effect of BIM-26100 on the in vivo growth of the SCLC tumor cell line described in Phase 6. Twenty athymic nude females, 5 to 6 weeks of age, were implanted on day 0 with the NCI-H69 human SCLC, individually identified and then randomized into the following vehicle control and test groups: Group No. Treatment No. Animals 1 Saline vehicle treated control: 0.2 ml, s.c. inf., b.i.d., QD1-28 10 2 BIM-26100: 50ug/inj . , s.c, b.i.d., Q 1-28 5 3 BIM-26100: 50ug/inj., s.c. inf., b.i.d., QD1-28 5 (s.c. = subcutaneously; inj . = injected; b.i.d. = twice per day; QD1-28 = daily treatment, on days 1 - 28.) Growth of NCI-H69 xenografts and the tumor growth inhibitory activity of the bombesin antagonist BIM-26100 (pGlu-Gln-Trp-Ala-Val-Gly-His-Pheψ[CH-.NH]Leu-NH 2 ) are illustrated as tumor growth curves in Fig. 1, and relative tumor sizes in Table II. Administration of BIM-26100 as a s.c. infusion around the tumor significantly inhibited tumor growth. The effectiveness of the antitumor activity of BIM-26100 is evident in view of the large inoculum of NCI-H69 tumor cells (i.e., the equivalent of 5 confluent 75 cm cell culture flasks per animal) and the agglomerated condition of the cells. In confluent flasks, NCI-H69 agglomerates are macroscopically visible and together resemble a metastatic tumor colony. Many such tumor colonies were implanted per animal. The dose of BIM-26100 was arbitrarily selected on the basis of compound availability and is not optimal. Higher doses of BIM-26100 may be administered, as indicated by body weight gain (minus tumor weight) gain during the course of treatment (Table III). This suggest BIM-26100 completely lacks local or systemic toxicity and is useful therapeutically as an anti-growth factor wuth anti-tu or effects. Fig. 3 shows the effect of the bombesin antagonist D-p-Cl-Phe-Gln-Trp-Ala-Val-Gly-His-Leuψ[CH 2 NH]Phe-NH 2 on bombesin-stimulated amylase secretion in the rat. The results show that this analog is a potent antagonist; 5 nM of the analog can inhibit the secretion of anylase stimulated by 0.5 nM of bombesin for 150 minutes after bolus injection. 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 transmucσsally) , in a sustained release formulation using a biodegradable biocompatible polymer, or by on-site delivery (e.g., in the case of anti-cancer bombesin to the lungs) using micelles, gels and liposomes. The bombesin antagonists of the invention are suitable for the treatment of all -forms of cancer where bombesin-related substances act as autocrine or paracrine mitotic agents, particularly small-cell lung carcinoma. The peptides can also be used for the inhibition of gastric acid secretion and motility disorders of the GI tract, the symptomatic relief and/or treatment of exocrine pancreatic adenocarcinoma, and the restoration of appetite to cachexic patients. The peptides can be administered to a human patient in a dosage of 0.5 μg/kg/day to 5 mg/kg/day. For some forms of cancer, e.g., small cell lung carcinoma, the preferred dosage for curative treatment is 250mg/patient/day. Table 1 3T3 GRP Thym. Receptor Uptake Code Structure IC50(nM) IC50(nM) BIM-26092 Gly-Asn-His-Trp-Ala-Val-Gly- His-Leuψ[CH 2 NH]Leu-NH 2 Neuromedin C 242 466 BIM-26095 pGlu-Gln-Trp-Ala-Val-D-Ala- His-Leuψ[CH 2 _IH]Leu-NH 2 - - Litorin — ^ --" 1 2623 1209 BIM-26100 pGlu-Gln-Trp-Ala-Val-Gly-His- PheψCCH 2 NH] eu-NH 2 Litorin 23 26 BIM-26101 pGlu-Gln-Trp-Ala-Val-Gly-His- Leuψ[CH 2 NH]Leu-NH 2 Litorin 118 296 BIM-26105 D-Ala-Asn-His-Trp-Ala-Val- D-ALa-His-Leuψ[CH 2 CH]Leu- ' NH 2 Neuromedin C 107 107 BIM-26106 desGly-D-Ala-His-Trp-Ala-Val- D-Ala-His-Leuψ[CH 2 NH]Met-NH 2 Neuromedin C 401 354 BIM-26107 D-Phe-His-Trp-Ala-Val-Gly- His-Leuψ[CH 2 NH]Leu-NH 2 Neuromedin C 199 154 Table 1 (cont'd) 3T3 GRP Thym. Receptor Uptake Code Structure IC50(nM) IC50(nM BIM-26108 N-Ac-D-Ala-His-Trp-Ala-Val- Gly-His-Leuψ[CH 2 NH]Leu-NH 2 Neuromedin C 841 >1000 BIM-26113 D-Phe-Gln-Trp-Ala-Val-Gly- His-Leuψ[CH 2 NH]Leu-NH 2 Litorin 5.8 9 BIM-26114 D-Nal-Gln-Trp-Ala-Val-Gly- His-Leuψ[CH 2 NH]Leu-NH 2 Litorin 23.5 28 BIM-26120 pGlu-Gln-Trp-Ala-Val-Gly- His-Sta-NH 2 Litorin 150 165 BIM-26122 D-Phe-Gln-Trp-Ala-Val-Gly- His-Leu-NH 2 Litorin 5.9 28.6 BIM-26136 D-Nal-Gln-Trp-Ala-Val-Gly-His- Leuψ[CH 2 NH]Phe-NH 2 Litorin 1.4 3. BIM-26182 D-Cpa-Gln-Trp-Ala-Val-Gly-His- 0.88 4. β-Leu-NH 2 Litorin Table II )TN VIVO TUMOR INHIBITORY ACTIVITY OF THE BOMBESIN ANTAGONIST BIM-26100: NCl-IK? HUMAN SCLC Group Tumor Size 1 % Tumor Size % Nfl. T iatinent Pay 18 fmm. Tcst/ϋo rol Day 28 fmm) Test/Control 1 Vehicle treated control, 0.2ml. t.c Inf.. b . QD1-28 2 BIM-26100. SOμgfin . . QD1-28 3 BIM-26100. 50μg/inJ ^ SΛ. int. b-Ld . QD1 -28 *Da repotted as means ±. SD on 10 animals tn the control and 5 in test groups. Student's t Test significance of difference from control: *p<0.05: **ρ<0.0L

Claims: Claims x- 1. A linear peptide which is an analog of 2 naturally occurring, biologically active amphibian 3 bombesin or mammalian GRP having an active site and a -* binding site responsible for the binding of said peptide 5 to a receptor on a target cell, cleavage of a peptide 6 bond in said active site of naturally occurring bombesin 7 or GRP being unnecessary for in vivo biological 8 activity, said analog having one of the following 9 modifications: (a) a deletion of a residue within said 10 active site and a modification of a residue outside of 11 said active site, or (b) a replacement of one or two 12 residues within said active site with a synthetic amino 13 acid, said analog being capable of binding to said 14 receptor so that said analog is capable of acting as a 15 competitive inhibitor of said naturally occurring 16 peptide by binding to said receptor and, by virtue of 17 one of said modifications, failing to exhibit the in 18 vivo biological activity of said naturally occurring 19 bombesin or GRP. 1 2. The linear peptide of claim 1 wherein said active site comprises at least one amino acid in the 3 carboxy terminal half of the peptide, said linear 4 peptide including said amino acid in its carboxy 5 terminal half. 1 3. The linear peptide of claim 1 wherein said 2 active site includes at least one amino acid in the 3 amino terminal half of the peptide, said linear peptide 4 including said amino acid in its amino terminal half. _ 46 _ 4. A therapeutic peptide comprising between seven and nine amino acid residues, inclusive, said peptide being an analog of one of the following naturally occurring peptides terminating at the carboxy-terminus with a Met residue: (a) litorin; (b) neuromedin; (c) the ten amino acid carboxy-terminal region of mammalian gastrin releasing peptide; and (d) the ten amino acid carboxy-terminal region of amphibian bombesin, said therapeutic peptide being of the formula: wherein A = Gly, Hie, α-aminobutyric acid, or the D-isomer of any of Ala, Val, Gin, Asn, Leu, lie, Met, p-X-Phe (where X = F, Cl, Br, 0 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal, or is deleted; A = the D- or L-isomer of any of pGlu, Nle, or α-aminobutyric acid, or the D-isomer of any of Ala, Val, Gin, Asn, Leu, lie, Met, p-X-Phe (where X = F, Cl, Br, 0 2 , OH, H or CH 3 >, Trp, Cys, or β-Nal, or is deleted; A 2 = pGlu, Gly, Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl; Br, 0 2 , OH, H or ^3)' Tr P' Cys, β-Nal, His, 1-methyl-His, or 3-methyl-His; A 4 = Ala, Val, Gin, Asn, Gly, Leu, He, Nle, α-aminobutyric acid. Met, p-X-Phe (where X = F, Cl, Br, N0 2 , OH, H or CH 3 ), Trp, Cys, or β -Nal; _ 47 _ A = Gin, Asn, Gly, Ala, Leu, lie, Nle, α-amincbutyric acid, Met, Val, p-X-Phe (where X = F, Cl, Br, OH, H or CH 3 ), Trp, Thr , or A = Sar, Gly, or the D-isomer of any of Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br, N0 2 , OH, H or CH 3 ), Trp, Cys, or A - 1-methyl-His, 3-methyl-His, or His; provided that if A is present, A cannot be pGlu; 0 1 __ and if A or A is present, A cannot be pGlu; and when A is deleted and A 1 is pGlu, R. must be H and R 2 must be the portion of Glu that forms the imine ring in pGlu; and further provided that W can be: wherein R a- is CKR. Li .-(CH- Z) Til . (where n 14. is either H or OH; and nl may be either of 1 or 0), or is deleted, and Z χ is the identifying group of any one of the amino acids Gly, Ala, cyclohexyl-Ala, Val, Leu, He, ser, Asp, Asn, Glu, Gin, p-X-Phe (where X - H, F, Cl, Br, N0 2 , OH, or CH 3 ), Trp, Cys, Met, Pro, HyPro, or isopropyl, cyclohexylmethyl, β-nal, β-napthylmethyl, or phenylmethyl; and V is either where R 4 is any of C 1 _ 2Q alkyl, C 3 _ 2Q alkenyl, C 3_20 alfcinyl, phenyl, napthyl, or C ? _ 10 phenylalkyl, and each R , and R g , independently, is any of H, C 1 _ 12 alkyl, C ? _ 10 phenylalkyl, lower _ 48 _ acyl, or R. β N \ K where R 15 is any cf H, C 1 _ 12 alkyl, C 7 _ 1Q phenylalkyl, or lower acyl; provided that when one of R- or R, is NHR,., the other is H; and provided that any asymmetric carbon atom can be R, S or a racemic mixture; and further provided that each R, and R 2 , independently, is K, C 1 _ 12 alkyl, C 7 _ 1Q phenylalkyl, COE. ^ (where E 1 is C, 2 - alkyl, C,_ 2Q alkenyl, C 3- 20 a ^ k ^ Ii y . 1 ' phenyl, naphthyl, or C 7 _ 1Q phenylalkyl), or lower acyl, and R, and R 2 are bonded to the N-terminal amino acid of said peptide, and further provided that when one of R, or 2 is COE- ^ , the other nust be H, or a pharmaceutically acceptable salt thereof. 5. The therapeutic peptide of claim 4 wherein A = Gly, D-Phe, or is deleted; A = p-Glu, D-Phe, D-Ala, D-β-Nai, D-Cr.a, or D-Asn; 2 A = Gin, His, 1-πethyl-His, or 3-methyl-His; A 4 = Ala; A 5 = Val; A 6 = Sar, Gly, D-Phe, or D-Ala; A 7 = His; provided that where 3 is CH 2 ~CH 2 , Z χ is the identifying group of Leu or Phe; , or where R 3 is CH 2 , Z l is the identifying group of β-Leu or Leu; or where R 3 is CKOH-CH 2 , Z χ is the identifying group of Leu ~ or is isopropyl, cyclohexylmethyl, β-naphthylmethyl, or phenylmethyl; provided that where V is R ς / 3 N . each R 5- and R o, is K . 6. The t herapeutic peptide of claim 5 wherein v i s NHR g and R g is H. 7. The therapeutic peptide of claim 5 of the formula: pGlu-Gln-Trp-Ala-Val-Gly-His-statine-amide. 8. The therapeutic peptide of claim 5 of the ormula: D-p-Cl-?he-Gln-Trp-Ala-Val-Gly-His- β -Leu-NH.. 2 9. A therapeutic pepride comprising between e i ght and ten amino acid r'e"si4UduUBesS,, iinncclluussiivvee,, ssaaiidc peptide J D6inσ an __«5l«__. -m- _ _. s cemg an analog of one 0 £ the following naturally 4 occurring peptides terminating at the oarbo K y-terminus 5 w i th a Met residue: ( a ) litorin; <b> neuromedin ; ( o ) the 6 ten aπuno acid carboxy-terminal region of mammalian 7 gastπn releasing peptide; and (d) the ten amino acid 8 carboxy-terminal region of amphibian bombesin. said 9 therapeutic peptide being of the formula: 1 wherein 14 _0 15 ~ Gly ' Nle ' *-am -obu y ic acid, or the D-isomer i6 of any of Ala, Val, Gin, Asn, Leu, He, Met, ^ P-X-Phe ( where X = F , Cl, Br, N0 2 , OH, H or < V' Tr ?' Cys, or β -Nal, or is deleted; 18 the D- or L-isomer cf any of pGlu, N le, cr 19 α-amincbutyric acid, or the D-isomer of any cf 20 Ala, val, Gin, Asn, Leu, He, Met, p-X-?he (where 21 X = F, Cl, 3r, N0 2 , OH, H or α , Trp, Cys, 22 or β -Nal, or is deleted; 23 A = PGlu, Gly, Ala, Val, Gin, Asn, Leu, He, Met, 24 P-X-Phe (where X = F, Cl, Br, 25 N0 2 , OH, H or CH CH 3 ), Trp, cys, β -Nal, His, 1-methyl-His, or 26 3-methyl-His; 27 Ala, Val, Gin, Asn, Gly, Leu, He, Nle, 28 α-aminobutyric acid. Met, p-X-Phe (where X = F, " ~ 1 a _ »TΛ Br ' S0 2' 0H ' H or CH.), Trp, Cys, or 30 - β 1--_NJ<al " ; J 31 32 Λ = Gln ' Asn - Q l7. Ala, Leu, He, Nle, 33 α-aminobutyric acid, Met, Val, p-X-Phe (where X 34 A 6 _ * F ' C ' Br ' 0H ' H or CH 3 ) , Trp, Thr, or β-Nal; Sar, Gly, or the D-isomer of any of Ala, V al , 35 Gin, Asn , Leu, He, Met, p-x-Phe (where X = F, 36 7 C1 ' Br ' N0 2' 0H ' H or CH ), Trp, Cys, or 37 β -Nal; 3 38 A , 0 1-πιethyl-His, 3-methyl-His, or His ; Jy provided that if i 0 ;„ 1 40 ^ A ° 1 Present, A 1 cannot be pGlu; and - A or A i s pres n . A 2 cannot be pGlu; and when 41 A ls deleted and A 1 is pGlu, R must be H and R, 42 must be the portion of Glu tha orms the imine ?ing in 43 PGlu ; and further provided that can be- 50 ,, ' P-X-Phe M ( V w Wi h l< e st r e e X == r Ht,, F F,, CCll,, BBrr,, NO., OH or CH,), r , 51 Cv«5 _ Ma n_._ -. _ * 3 * -r' cys Met. Pro. HyPro, cyclohexyl-Ala. or cyclohexylmethyl ; proved that vhere R 4 is CH.-MH and Z. is the "5 9r0UP °f * * ∞e ° f thβ am ' n ° aCl S Gly ' Ala ' oof t' ' he or a pharmaceutically acceptable salt thereof. 10. The therapeutic peptide of claim 9 wherein Λ = Gly, D-Phe, or is deleted; A = p-Glu, D-Phe, D-Ala, D-β-Nal, D-Cpa, or D-Asn; 2 A = Gin, His, 1-methyl-His, or 3-methyl-His; A 4 = Ala; A 5 = Val; A = Sar, Gly, D-Phe, or D-Ala; A 7 = His; where R 4 is CH 2 ~NH, each Z., is cyclohexylmethyl or is the identifying group of Leu or Phe; or Z 2 is the identifying group of Met, Leu or Phe. 11. The therapeutic peptide of claim 9 wherein A is D-β-Nal, each of Z._L and Z_£, independently, is Leu or Phe. 12. The therapeutic peptide of claim 11 of the formula: D- β -Nal-Gln-Trp-Ala-Val-Gly-His-Leuψ[CH 2 NH]Leu-NH 2 . 13. The therapeutic peptide of claim 11 of the formula: D- β -Nal-Gln-Trp-Ala-Val-Gly-His-Leuψ[CH 2 H3Phe-NH 2" 14. The therapeutic peptide of claim 9 wherein R R 44 iiss CCHH 22 -~NNHH,, aanndd ssaaiidd ccarbon atom bonded to Z 2 is of said R configuration. 15. The therapeutic peptide of claim 14 of the formula D-Phe-Gln-Trp-Ala-Val-Gly-His-Leuψ[CH 2 NH]-D-Phe-NH 2 . 16 . The therapeutic peptide of claim 9 where A or A is a D amino acid and V is OR 4, . 1 7 . The t herapeutic peptide of claim 16 cf t he formula : 3-Phe-Gln-Trp-Ala- V al-Gly-His-Leu-Met-methylester . 18. A therapeutic peptide comprising between seven and nine amino acid residues, inclusive, said peptide being an analog of one of the following naturally occurring peptides terminating at the carboxy-terminus with a Met residue: (a) litorin ; ( b ) neuromedin; (c ) the ten amino acid carboxy-terminal reg i on of mammalian gastrin releasing peυtide ; and ( d ) the ten amino acid carboxy-terminal region of amnhibian ∞moes i n. said therapeutic peptide being of the formula: >°-A 1 -A 2 -Trp-A 4 -A 5 -A 6 -A 7 -W / wnerein ,0 Gly, Nle, α-aminobutyric acid, or the D-isomer of any cf Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br, NO-,, OH, H or CH 3 ), Trp, Cys, or β-Nal, or is deleted; A = the D- or L-isomer of any of pGlu, Nle, or α-aminobutyric acid, or the D-isomer of any of Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br, N0 2 , OH, H or CH 3 ), ,2 Trp, Cys, or β-Nal, or is deleted; pGlu, Gly, Ala, Val, Gin, Asn, Leu, lie, Met, p-X-?he ( where X = F, Cl, Br, N0 2 , OH, H or r>v \ CH 3 ) , Trp, cys, β -Nal, His, 1-methyl-His, or 3-methyl-His; Phenylalkyl), cr lower acyl, and R_ and R, are ponded to the N-.ermmal amino acid of said pe^ide, and rurther provided that when one of R, or R is " C0E χ , the other mus- be H, or a pharmaceuticall y acceptable salt thereof. ,0 19' The tiιer apeutic peptide of claim 18 wherein « ι - Gly, D-Phe, or is deleted; A 2 = p-Glu, D-Phe, D-Ala, D-β-Nal, D-Cpa, or D-Asn ; * 4 = Gin, His, 1-methyl-His, or 3-methyl-His; A == Ala; A Val; A = Sar, Gly, D-Phe, or D-Ala; A' = His; provided that Z χ is the identifying group of any one of the amino acids Leu or D or L p-X-Phe (where X . H, - Cl, Br, N0 2 , OH or CH 3 ) ; and each R. , R_ Q and i ndependently, is H , lower alkyl, lowe? pnenylalkyl, or lower naphthylalkyl. 20. The therapeutic peptide of claim 19 vnerein Z ∑ is Leu, Rg is H , and each R .. and R T1 IS lower alkyl. 10 l l 21 - The therapeutic peptide of claim 20 of the -ormula: D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-ethylamide. , - 22 ' ThS thera Peu ic peptide of claim 20 of the -ormui : D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NH.. 23. A therapeutic peptide comprising between six and eight amino acid residues, inclusive, said peptide being an analog of one of the following naturally occurring peptides terminating at the carboxy-terminus with a Met residue: (a) litorin; (b) neuromedin; (c) the ten amino acid carboxy-terminal region of mammalian gastrin releasing peptide; and (d) the ten amino acid carboxy-terminal region of amphibian bombesin, said therapeutic peptide being of the formula: wherein A = Gly, Nle-, α-aminobutyric acid, or the D-isomer of any of Ala, Val, Gin,.Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br, NO-,, OH, H or CH.), Trp, Cys, or β-Nal, or is deleted; A = the D- or L-isomer of any of pGlu, Nle, or α-aminobutyric acid, or the D-isomer of any of Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br, N0 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal, or is deleted; A = pGlu, Gly, Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X « F, Cl,- Br, N0 2 , OH, H or CH 3>' Tr P' c y s ' β -Nal, His, 1-methyl-His, or 3-methyl-His; 4 = Ala, Val, Gin, Asn, Gly, Leu, He, Nle, α-aminobutyric acid, Met, p-X-Phe (where X = F, Cl, 3r, N0 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal ; = Gin, Asn , Gly, Ala , Leu , He , Nle , α-aminobutyr ic acid , Met , Val , p-X-Phe ( where X = F , Cl , 3r , OH , H or CH 3 ) , Trp , Thr , or A - Sar, Gly, or the D-isomer of any of Ala, Val, Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br, N0 2 , OH, H or CH 3 ), Trp, Cys, or 3-Nal; A = 1-methyl-His, 3-methyl-His, or His; provided that if A is present, A cannot be pGlu; 0 1 2 and- if A or A is present, A cannot be pGlu; 'and when A is deleted and A is pGlu, R. must be H and 2 must be the portion of Glu that forms the imine ring in pGlu; and further provided that W can be: wherein each 12 and R..,, independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl; provided that any asymmetric carbon atom can be R, S or a racemic mixture; and further provided that each R. and R 2 , independently, is H, C 1 _ 12 alkyl, C 7 _ 10 phenylalkyl, COE. ^ (where E χ is C 1-2Q alkyl, 3-20 all£ enyl, C 3-20 alkin y 1 ' phenyl, naphthyl, or C 7_ιo phenylalkyl), or lower acyl,* and R-, and R 2 are bonded to the N-terminal amino acid of said peptide, and further provided that when one of R. or R 2 is C0E 1 , the other must be H, or a pharmaceutically acceptable salt thereof. - 58 ~ 24. The therapeutic peptide of claim 23 wherein A = Gly, D-Phe, or is deleted; A 1 = p-Glu, D-Phe, D-Ala, D-β-Nal, D-Cpa, or D-Asn; A 2 = Gin, His, 1-methyl-His, or 3-methyl-His; A 4 = Ala; A 5 = Val; A = Sar, Gly, D-Phe, or D-Ala; A 7 = His; where each R- 2 and R 13 , is H; and each ^ ^ and R , independently, is H, lower alkyl, or lower acyl. 25. The therapeutic peptide of claim 24 7 wherein either of N.., or N.- is other than H, A must be His, A 6 must be Gly, A5 must be Val, A4 2 must be Ala, and A must be His. 26. The therapeutic peptide of claim 24 wherein either of R. or » is other than H, A must not be deleted. 27. The therapeutic peptide of claim 4, 9, 18, or 23 wherein said analog is at least 25% homologous with said naturally occurring peptide. ' 28. The therapeutic peptide of claim 27 wherein said analog is at least 50% homologous with said naturally occurring peptide. 29. A bombesin therapeutic peptide of the formula: pGlu-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His- Statine. 30. An effective bombesin antagonistic peptide containing the amino acid formula: l- A 2- A 3_ A 4_ A 5_ A 6_ A 7_ A 8. A 9. A 10_ / wherein A = pGlu, D or L, or is deleted; 2 A = Gin, Asn, Gly, Ala, Leu, He, Nle, α-aminobutyric acid, Met, Val, Phe, p-X-Phe (X = F, Cl, Br, OH or CHg), Trp, β-naphthylalanine or is deleted; 3 A = Arg, D-Arg, Lys, D-Lys or is deleted; 4 A = Gin, Asn, Gly, Ala, Leu, He, Nle, α-aminobutyric acid, Met, Val, Phe, p-X-Phe (X = F, Cl, Br, OH or CH 3 ), Trp, β-naphthylalanine or is deleted ; A 5 » Gin, Asn, Gly, Ala, Leu, He, Nle, α-aminobutyric acid, Met, Val, Phe, D-Phe, p-X-Phe (X = F, Cl, Br, OH or CH-), Trp, β-naphthylalanine, D-Ala or is deleted; A = Gin, Asn, Gly, Ala, D-Ala, N-Ac-D-Ala, Leu, He, Nle, α-aminobutyric acid, Met, Val, Phe, p-X-Phe (X - F, Cl, Br, OH or CH 3 ), Trp, p-Glu, β-naphthylalanine or is deleted; A 7 = Gin, Asn, Gly, Ala, Leu, He, Nle, α-aminobutyric acid, Met, Val,: Phe, D-Phe, p-X-Phe (X = F, Cl, Br, OH or CH 3 ), Trp, Lys, His, or β-naphthyl lanine; A 8 = Trp or Met; ~~^ - 60 - A = Gin, Asn, Gly, Ala, Leu, He, Nle, α-aminobutyric acid, Met, Val, Phe, p-X-Phe (X = F, Cl, Br, OH or OL-), Trp, or β-naphthylalanine, D or L; A 10 = Gin, Asn, Gly, Ala, Leu, He, Nle, α-aminobutyric acid, Met, Val, Phe, p-X-Phe (X = F, Cl, Br, OH or CH 3 ), Trp, Thr, or β-naphthy 1 1 anine ; A 11 = Gly, Phe, D or L; A 12 = His, Phe, or p-X-Phe (X = F, Cl, Br, OH, CH , D or ; A i0 = Gin, Asn, Gly, Ala, Leu, He, Nle, α-aminobutyric acid, Met, Val, Phe, p-X-Phe (X = F, Cl, Br, OH or CH 3 ), Trp, or β-naphthylalanine; A 14 = Gin, Asn, Gly, Ala, Leu, He, Nle, α-aminobutyric acid, Met, Val, Phe, p-X-Phe (X = F, Cl, Br, OH or CH 3 , Trp,. or β -naphthylalanine; provided that each R χ , R 2 , R. , and R., independently, is H, C 1-12 alkyl, C 7 _ 1Q phenylalkyl, COE^ ^ (where E χ is C 1 _ 2(J alkyl, C 3 _ 2(J alkenyl, C-,_ 20 al&inyl, phenyl, naphthyl, or C ? _ 10 phenylalkyl), or COOE 2 (where E 2 is C 1 _ 1(J alkyl or C- ,- phenylalkyl), and R. and R, are bonded to the N-terminal amino 1 2 3 acid of said peptide, which can be A , A , A , A R m *~f A , A , A , or A , and further provided that when one of R j^ or R 2 is COE, or COOE 2 , the other must be H, and when one of R 3-, or R4. is COE n 1 or C00E 2 , the other must be H, and further provided that when A = pGlu, R χ must be H and R 2 must be the portion of Glu that forms the imine ring in pGlu; and for each of the residues A 7 , A 8 , A 9 , A 11 , A 12 , 13 . . . and A , independently, the carbon atom participating in the amide bond between that residue and the nitrogen atom of the alpha amino group of the adjacent amino acid residue may be a carbonyl carbon or may be reduced to a methylene carbon, provided that at least one such carbon atom must be reduced to a methylene carbon, said peptide further comprising n A 5 = Cys; A = Cys or a D-isomer of any of said amino acids ; A = pGlu, Cys , 1-methyl-His , or 3-methyl-His ; A 9 = Cys ; A Sar , or the D-isomer of any of Ala , Val , Gin, Asn, Leu, He, Met, p-X-Phe (where X = F, Cl, Br, N0 2 , OH, or CH 3 ), Trp, Cys, or β-Nal; A 12 - l-methyl-His, or 3-methyl-His; 14 and where A may be deleted. 31. The therapeutic peptide of claim 30 of the formula: D-p-Cl-Phe-Gln-Trp-Ala-Val-Gly-His-Leuψ[CH 2 NH]Phe-NH 2

Inventors: COY DAVID H, KIM SUN HYUK, MOREAU JACQUES-PIERRE, TAYLOR JOHN E, COY, DAVID, H., KIM, SUN, HYUK, MOREAU, JACQUES-PIERRE, TAYLOR, JOHN, E.
Applicants: UNIV TULANE, ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND
Application year: 1989
Main classification: C07K7
IPC codes: A61K31, A61K38, A61P1, A61P5, A61P9, A61P35, C07K7, C07K14