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Details for Patent: 4,595,676

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Details for Patent: 4,595,676

Title: Rat hypothalamic GRF
Abstract:Rat hypothalamic GRF has been synthesized and has the formula: H-His-Ala-Asp-Ala-Ile-Phe-Thr-Ser-Ser-Tyr-Arg-Arg-Ile-Leu-Gly-Gln-Leu-Tyr- Ala-Arg-Lys-Leu-Leu-His-Glu-Ile-Met-Asn-Arg-Gln-Gln-Gly-Glu-Arg-Asn-Gln-Glu -Gln-Arg-Ser-Arg-Phe-Asn-OH. The peptide is believed to be and is hereinafter referred to as rhGRF (for rat hypothalamic GH releasing factor). The invention provides synthetic peptides which are extremely potent in stimulating the release of pituitary GH in animals and which have the formula: H-R.sub.1 -Ala-Asp-Ala-Ile-Phe-Thr-R.sub.8 -Ser-R.sub.10 -Arg-R.sub.12 -R.sub.13 -Leu-R.sub.15 -Gln-Leu-R.sub.18 -Ala-Arg-Lys-Leu-Leu-R.sub.24 -R.sub.25 -Ile-R.sub.27 -R.sub.28 -Arg-Gln-Gln-Gly-Glu-R.sub.34 -Asn-Gln-Glu-R.sub.38 -R.sub.39 -R.sub.40 -Arg-R.sub.42 -R.sub.43 -R.sub.44 -Y wherein R.sub.1 is Tyr, Met, D-Tyr, Leu, D-His or His; R.sub.8 is Ser or Asn; R.sub.10 is Tyr or D-Tyr; R.sub.12 is Arg or Lys; R.sub.13 is Ile or Val; R.sub.15 is Gly or D-Ala; R.sub.18 is Tyr or Ser; R.sub.24 is His or Gln; R.sub.25 is Glu or Asp; R.sub.27 is Met, Ala, Nle, Ile, Leu or Val; R.sub.28 is Asn or Ser; R.sub.34 is Arg or Ser; R.sub.38 is Gln or Arg; R.sub.39 is Arg or Gly; R.sub.40 is Ser or Ala; R.sub.42 is Phe or Ala; R.sub.43 is Asn or Arg; R.sub.44 is a natural amino acid or des-R.sub.44 ; and Y signifies the carboxyl moiety of the amino acid residue at the C-terminus and is the radical --COOR,--CRO,--CONHNHR,--CON(R)(R') or --CH.sub.2 OR, with R and R' being lower alkyl, fluoro lower alkyl or hydrogen. These peptides or biologically active fragments thereof, or analogs thereof having well-known substitutions and/or additions, as well as nontoxic salts of any of the foregoing, may be administered to animals, including humans, to stimulate the release of GH and may be used diagnostically.
Inventor(s): Spiess; Joachim (Encinitas, CA), Rivier; Jean E. F. (La Jolla, CA), Vale, Jr.; Wylie W. (La Jolla, CA)
Assignee: The Salk Institute for Biological Studies (San Diego, CA)
Filing Date:Apr 26, 1983
Application Number:06/488,748
Claims:1. A synthetic peptide having the formula: H-R.sub.1 -Ala-Asp-Ala-Ile-Phe-Thr-R.sub.8 -Ser-R.sub.10 -Arg-R.sub.12 -R.sub.13 -Leu-R.sub.15 -Gln-Leu-R.sub.18 -Ala-Arg-Lys-Leu-Leu-R.sub.24 -R.sub.25 -Ile-R.sub.27 -R.sub.28 -Arg-Gln-Gln-Gly-Glu-R.sub.34 -Asn-Gln-Glu-R.sub.38 -R.sub.39 -R.sub.40 -Arg-R.sub.42 -R.sub.43 -R.sub.44 -Y wherein R.sub.1 is Tyr, Met, Leu, D-Tyr, D-His or His; R.sub.8 is Ser or Asn; R.sub.10 is Tyr or D-Tyr; R.sub.12 is Arg or Lys; R.sub.13 is Ile or Val; R.sub.15 is Gly or D-Ala; R.sub.18 is Tyr or Ser; R.sub.24 is His or Gln; R.sub.25 is Glu or Asp; R.sub.27 is Met, Ala, Nle, Ile, Leu or Val; R.sub.28 is Asn or Ser; R.sub.34 is Arg or Ser; R.sub.38 is Gln or Arg; R.sub.39 is Arg or Gly; R.sub.40 is Ser or Ala; R.sub.42 is Phe or Ala; R.sub.43 is Asn or Arg; R.sub.44 is a natural amino acid or des-R.sub.44 ; and Y represents the carboxyl moiety of the amino acid residue at the C-terminus and is the radical --COOR,--CRO,--CONHNHR, --CON(R)(R') or --CH.sub.2 OR, with R and R' being lower alkyl, fluoro lower alkyl or hydrogen, or a fragment thereof extending from the N-terminus in a continuous sequence to a residue in position 27 through 42 at its C-terminus, which fragment is biologically active to cause the release of GH from the pituitary, or a nontoxic salt thereof provided however that any one of the following is present, R.sub.8 is Ser, R.sub.12 is Arg, R.sub.13 is Ile, R.sub.18 is Tyr, R.sub.24 is His, R.sub.25 is Glu, R.sub.28 is Asn, R.sub.34 is Arg, R.sub.38 is Gln, R.sub.39 is Arg, R.sub.40 is Ser, R.sub.42 is Phe or R.sub.43 is Asn.

2. The peptide of claim 1 wherein Y is CONH.sub.2.

3. The peptide of claim 1 wherein R.sub.8 is Ser.

4. The peptide of claim 1 wherein R.sub.1 is Tyr.

5. The peptide of claim 1 wherein R.sub.1 is His.

6. The peptide of claim 1 wherein R.sub.1 is Met and R.sub.27 is other than Met.

7. The peptide of claim 6 wherein R.sub.27 is Leu.

8. The peptide of claim 1 wherein R.sub.13 is Ile.

9. The peptide of claim 1 wherein R.sub.44 is Val.

10. The peptide of claim 1 wherein R.sub.1 is D-His.

11. The peptide of claim 1 wherein R.sub.10 is D-Tyr.

12. The peptide of claim 10 wherein R.sub.10 is D-Tyr.

13. The peptide of claim 1 wherein R.sub.27 is Nle.

14. The peptide of claim 1 wherein R.sub.1 is His, R.sub.8 is Ser, R.sub.10 is Tyr, R.sub.12 is Arg, R.sub.13 is Ile, R.sub.15 is Gly, R.sub.18 is Tyr, R.sub.24 is His, R.sub.25 is Glu, R.sub.27 is Met, R.sub.28 is Asn, R.sub.34 is Arg, R.sub.40 is Ser, R.sub.42 is Phe, R.sub.43 is Asn, R.sub.44 is des-R.sub.44 and Y is --COOH or --CONH.sub.2.

15. A pharmaceutical composition for stimulating the release of GH in an animal comprising an effective amount of the peptide of claim 1 or a nontoxic salt thereof, and a pharmaceutically or veterinarily acceptable liquid or solid carrier therefor.

16. A method of stimulating the release of growth hormone in an animal, which comprises administering to said animal an effective amount of a synthetic peptide having the formula: H-R.sub.1 -Ala-Asp-Ala-Ile-Phe-Thr-R.sub.8 -Ser-R.sub.10 -Arg-R.sub.12 -R.sub.13 -Leu-R.sub.15 -Gln-Leu-R.sub.18 -Ala-Arg-Lys-Leu-Leu-R.sub.24 -R.sub.25 -Ile-R.sub.27 -R.sub.28 -Arg-Gln-Gln-Gly-Glu-R.sub.34 -Asn-Gln-Glu-R.sub.38 -R.sub.39 -R.sub.40 -Arg-R.sub.42 -R.sub.43 -R.sub.44 -Y wherein R.sub.1 is Tyr, Met, Leu, D-Tyr, D-His or His; R.sub.8 is Ser or Ans; R.sub.10 is Tyr or D-Tyr; R.sub.12 is Arg or Lys; R.sub.13 is Ile or Val; R.sub.15 is Gly or D-Ala; R.sub.18 is Tyr or Ser; R.sub.24 is His or Gln; R.sub.25 is Glu or Asp; R.sub.27 is Met, Ala, Nle, Ile, Leu or Val; R.sub.28 is Asn or Ser; R.sub.34 is Arg or Ser; R.sub.38 is Gln or Arg; R.sub.39 is Arg or Gly; R.sub.40 is Ser or Ala; R.sub.42 is Phe or Ala; R.sub.43 is Asn or Arg; R.sub.44 is a natural amino acid or des-R.sub.44 ; and Y represents the carboxyl moiety of the amino acid residue at the C-terminus and is the radical --COOR, --CRO, --CONHNHR, --CON(R)(R') or --CH.sub.2 OR, with R and R' being lower alkyl, fluoro lower alkyl or hydrogen, provided however that either R.sub.8 is Ser, R.sub.12 is Arg, R.sub.13 is Ile, R.sub.18 is Tyr, R.sub.24 is His, R.sub.25 is Glu, R.sub.28 is Asn, R.sub.34 is Arg, R.sub.38 is Gln, R.sub.39 is Arg, R.sub.40 is Ser, R.sub.42 is Phe or R.sub.43 is Asn or a fragment thereof extending from the N-terminus in a continuous sequence to a residue in position 27 through 42 at its C-terminus, which fragment is biologically active to cause the release of GH from the pituitary, or a nontoxic salt thereof.

17. A method in accordance with claim 16 wherein said administering is carried out either intravenously, subcutaneously, intramuscularly, percutaneously or orally.

18. A method in accordance with claim 16 wherein R.sub.1 is His, R.sub.8 is Ser, R.sub.10 is Tyr, R.sub.12 is Arg, R.sub.13 is Ile, R.sub.15 is Gly, R.sub.18 is Tyr, R.sub.24 is His, R.sub.25 is Glu, R.sub.27 is Met, R.sub.28 is Asn, R.sub.34 is Arg, R.sub.40 is Ser, R.sub.42 is Phe, R.sub.43 is Asn, R.sub.44 is des-R.sub.44 and Y is --COOH or --CONH.sub.2.

19. A method in accordance with claim 18 wherein the peptide has the formula H-His-Ala-Asp-Ala-Ile-Phe-Thr-Ser-Ser-Tyr-Arg-Arg-Ile-Leu-Gly-Gln- Leu-Tyr-Ala-Arg-Lys-Leu-Leu-His-Glu-Ile-Met-Asn-Arg-Gln-Gln-Gly-Glu-Arg-Asn -Gln-Glu-Gln-Arg-Ser-Arg-Phe-Asn-OH.

20. A method for the therapeutic treatment of humans in accordance with claim 16.

21. A method for promotion of growth in warm-blooded nonhuman animals in accordance with claim 16.

22. A method for growth promotion in agriculture in accordance with claim 16.

23. An intermediate peptide having the formula: H-Met-R.sub.1 -Ala-Asp-Ala-Ile-Phe-Thr-R.sub.8 -Ser-Try-Arg-R.sub.12 -R.sub.13 -Leu-Gly-Gln-Leu-R.sub.18 -Ala-Arg-Lys-Leu-Leu-R.sub.24 -R.sub.25 -Ile-R.sub.27 -R.sub.28 -Arg-Gln-Gln-Gly-Glu-R.sub.34 -Asn-Gln-Glu-R.sub.38 -R.sub.39 -R.sub.40 -Arg-R.sub.42 -R.sub.43 -R.sub.44 -Y wherein R.sub.1 is Tyr, Leu or His; R.sub.8 is Ser or Asn; R.sub.12 is Arg or Lys; R.sub.13 is Ile or Val; R.sub.18 is Tyr or Ser; R.sub.24 is His or Gln; R.sub.25 is Glu or Asp; R.sub.27 is Ala, Ile, Leu or Val; R.sub.28 is Asn or Ser; R.sub.34 is Arg or Ser; R.sub.38 is Gln or Arg; R.sub.39 is Arg or Gly; R.sub.40 is Ser or Ala; R.sub.42 is Phe or Ala; R.sub.43 is Asn or Arg; R.sub.44 is a natural amino acid or des-R.sub.44 and Y represents the carboxyl moiety of the C-terminus residue and is either --COOH or --CONH.sub.2 or a fragment thereof extending from the N-terminus in a continuous sequence to a residue in position 27 through 42 at its C-terminus, which fragment is biologically active to cause the release of GH from the pituitary.

24. The peptide of claim 1 wherein R.sub.12 is Arg, R.sub.13 is Ile, R.sub.18 is Tyr, R.sub.24 is His, R.sub.25 is Glu, R.sub.28 is Asn, R.sub.34 is Arg, R.sub.38 is Gln, R.sub.39 is Arg, R.sub.40 is Ser, R.sub.42 is Phe or R.sub.43 is Asn.

25. The peptide of claim 24 wherein R.sub.27 is Leu.

26. The peptide of claim 23 wherein R.sub.1 is His, R.sub.8 is Ser, R.sub.12 is Arg, R.sub.13 is Ile, R.sub.18 is Tyr, R.sub.24 is His, R.sub.25 is Glu, R.sub.27 is Leu, R.sub.28 is Asn, R.sub.34 is Arg, R.sub.40 is Ser, R.sub.42 is Phe, R.sub.43 is Asn and R.sub.44 is des-R.sub.44.
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