IP Library › Granted Patent US 7,576,061

Granted Patent B2

US 7,576,061 · App. 10/771,232 · Granted Aug 18, 2009

Methods for preventing mitochondrial permeability transition

Assignees: Cornell Research Foundation, Inc.; Institute de Recherches Clinques de Montreal

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 7,576,061
App. No.: 10/771,232
Granted: Aug 18, 2009
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The invention provides a method of reducing or preventing mitochondrial permeability transitioning. The method comprises administering an effective amount of an aromatic-cationic peptide having at least one net positive charge; a minimum of four amino acids; a maximum of about twenty amino acids; a relationship between the minimum number of net positive charges (p m ) and the total number of amino acid residues (r) wherein 3p m is the largest number that is less than or equal to r+1; and a relationship between the minimum number of aromatic groups (a) and the total number of net positive charges (p t ) wherein 2a is the largest number that is less than or equal to p t +1, except that when a is 1, p t may also be 1.

Claims (368)

1. A method of reducing the number of mitochondria undergoing mitochondrial permeability transitioning (MPT), or preventing mitochondrial permeability transitioning in a mammal in need thereof, the method comprising administering to the mammal an effective amount of a peptide having the formula

D-Arg-Dmt-Lys-Phe-NH 2 ,

D-Arg-Dmt-Phe-Lys-NH 2 ,

D-Arg-Phe-Lys-Dmt-NH 2 ,

D-Arg-Phe-Dmt-Lys-NH 2 ,

D-Arg-Lys-Dmt-Phe-NH 2 ,

D-Arg-Lys-Phe-Dmt-NH 2 ,

Phe-Lys-Dmt-D-Arg-NH 2 ,

Phe-Lys-D-Arg-Dmt-NH 2 ,

Phe-D-Arg-Dmt-Lys-NH 2 ,

Phe-D-Arg-Lys-Dmt-NH 2 ,

Phe-Dmt-D-Arg-Lys-NH 2 ,

Phe-Dmt-Lys-D-Arg-NH 2 ,

Lys-Phe-Dmt-D-Arg-NH 2 ,

Lys-Dmt-D-Arg-Phe-NH 2 ,

Lys-Dmt-Phe-D-Arg-NH 2 ,

Lys-D-Arg-Phe-Dmt-NH 2 ,

Lys-D-Arg-Dmt-Phe-NH 2 ,

D-Arg-Dmt-D-Arg-Phe-NH 2 ,

D-Arg-Dmt-D-Arg-Dmt-NH 2 ,

D-Arg-Dmt-D-Arg-Tyr-NH 2 ,

D-Arg-Dmt-D-Arg-Trp-NH 2 ,

Trp-D-Arg-Phe-Lys-NH 2 ,

Trp-D-Arg-Tyr-Lys-NH 2 ,

Trp-D-Arg-Trp-Lys-NH 2 ,

Trp-D-Arg-Dmt-Lys-NH 2 ,

D-Arg-Trp-Lys-Phe-NH 2 ,

D-Arg-Trp-Phe-Lys-NH 2 ,

D-Arg-Trp-Lys-Dmt-NH 2 ,

D-Arg-Trp-Dmt-Lys-NH 2 ,

D-Arg-Lys-Trp-Phe-NH 2 ,

D-Arg-Lys-Trp-Dmt-NH 2 ,

Cyclohexyl-D-Arg-Phe-Lys-NH 2 , or

Ala-D-Arg-Phe-Lys-NH 2 .

2. A method according to claim 1 , wherein the peptide has the formula D-Arg-Dmt-Lys-Phe-NH 2 .

3. The method according to claim 1 , wherein the peptide is administered orally.

4. The method according to claim 1 , wherein the peptide is administered topically.

5. The method according to claim 1 , wherein the peptide is administered intranasally.

6. The method according to claim 1 , wherein the peptide is administered systemically.

7. The method according to claim 6 , wherein the peptide is administered intravenously.

8. The method according to claim 1 , wherein the peptide is administered subcutaneously.

9. The method according to claim 1 , wherein the peptide is administered intramuscularly.

10. The method according to claim 1 , wherein the peptide is administered intracerebroventricularly.

11. The method according to claim 1 , wherein the peptide is administered intrathecally.

12. The method according to claim 1 , wherein the peptide is administered transdermally.

13. The method according to claim 12 , wherein the transdermal administration is by iontophoresis.

14. The method according to claim 1 , wherein the mammal is suffering from ischemia.

15. The method according to claim 1 , wherein the mammal is suffering from reperfusion.

16. The method according to claim 1 , wherein the mammal is suffering from hypoxia.

17. The method according to claim 14 , wherein the ischemia is due to stroke.

18. The method according to claim 14 , wherein the ischemia is intestinal ischemia.

19. The method according to claim 14 , wherein the ischemia is present in a muscle tissue.

20. The method according to claim 19 , wherein the muscle tissue is cardiac muscle tissue.

21. The method according to claim 19 , wherein the muscle tissue is skeletal muscle tissue.

22. The method according to claim 19 , wherein the muscle tissue is smooth muscle tissue.

23. The method according to claim 1 , wherein the mammal is suffering from hypoxia.

24. The method according to claim 1 , wherein the mammal is suffering from drug-induced MPT.

25. The method according to claim 1 , wherein the mammal is a human.

26. A method of reducing the number of mitochondria undergoing mitochondrial permeability transitioning (MPT), or preventing mitochondrial permeability transitioning in a mammal in need thereof, the method comprising administering to the mammal an effective amount of a peptide having the formula

D-Arg-Dmt-Lys-Phe-NH 2 ,

D-Arg-Dmt-Phe-Lys-NH 2 ,

D-Arg-Phe-Lys-Dmt-NH 2 ,

D-Arg-Phe-Dmt-Lys-NH 2 ,

D-Arg-Lys-Dmt-Phe-NH 2 ,

D-Arg-Lys-Phe-Dmt-NH 2 ,

Phe-Lys-Dmt-D-Arg-NH 2 ,

Phe-Lys-D-Arg-Dmt-NH 2 ,

Phe-D-Arg-Dmt-Lys-NH 2 ,

Phe-D-Arg-Lys-Dmt-NH 2 ,

Phe-Dmt-D-Arg-Lys-NH 2 ,

Phe-Dmt-Lys-D-Arg-NH 2 ,

Lys-Phe-Dmt-D-Arg-NH 2 ,

Lys-Dmt-D-Arg-Phe-NH 2 ,

Lys-Dmt-Phe-D-Arg-NH 2 ,

Lys-D-Arg-Phe-Dmt-NH 2 ,

Lys-D-Arg-Dmt-Phe-NH 2 ,

D-Arg-Dmt-D-Arg-Phe-NH 2 ,

D-Arg-Dmt-D-Arg-Dmt-NH 2 ,

D-Arg-Dmt-D-Arg-Tyr-NH 2 ,

D-Arg-Dmt-D-Arg-Trp-NH 2 ,

Trp-D-Arg-Phe-Lys-NH 2 ,

Trp-D-Arg-Tyr-Lys-NH 2 ,

Trp-D-Arg-Trp-Lys-NH 2 ,

Trp-D-Arg-Dmt-Lys-NH 2 ,

D-Arg-Trp-Lys-Phe-NH 2 ,

D-Arg-Trp-Phe-Lys-NH 2 ,

D-Arg-Trp-Lys-Dmt-NH 2 ,

D-Arg-Trp-Dmt-Lys-NH 2 ,

D-Arg-Lys-Trp-Phe-NH 2 ,

D-Arg-Lys-Trp-Dmt-NH 2 ,

Cyclohexyl-D-Arg-Phe-Lys-NH 2 , or

Ala-D-Arg-Phe-Lys-NH 2 ,

wherein the peptide is administered to the mammal as a composition comprising a pharmaceutically acceptable carrier.

27. The method according to claim 26 , wherein the compound has the formula D-Arg-Dmt-Lys-Phe-NH 2 .

28. A method of reducing the number of mitochondria undergoing mitochondrial permeability transitioning (MPT), or preventing mitochondrial permeability transitioning in a mammal in need thereof, the method comprising administering to the mammal an effective amount of a peptide having the formula Phe-D-Arg-Phe-Lys-NH 2 or Dmp-D-Arg-Phe-Lys-NH 2 .

29. A method of reducing the number of mitochondria undergoing mitochondrial permeability transitioning (MPT), or preventing mitochondrial permeability transitioning in a mammal in need thereof, the method comprising administering to the mammal an effective amount of a peptide having the formula Phe-D-Arg-Phe-Lys-NH 2 or Dmp-D-Arg-Phe-Lys-NH 2 , wherein the peptide is administered to the mammal as a composition comprising a pharmaceutically acceptable carrier.

30. A method of reducing the number of mitochondria undergoing mitochondrial permeability transitioning (MPT), or preventing mitochondrial permeability transitioning in a mammal in need thereof, the method comprising administering to the mammal an effective amount of a peptide having the formula

Lys- D -Arg-Tyr-NH 2 ,

Phe- D -Arg-His,

D -Tyr-Trp-Lys-NH 2 ,

Trp- D -Lys-Tyr-Arg-NH 2 ,

Tyr-His- D -Gly-Met,

Phe-Arg- D -His-Asp,

Tyr- D -Arg-Phe-Lys-Glu-NH 2 (SEQ. ID. NO: 3),

Met-Tyr- D -Lys-Phe-Arg (SEQ. ID. NO: 4),

D -His-Glu-Lys-Tyr- D -Phe-Arg (SEQ. ID. NO: 5),

Lys- D -Gln-Tyr-Arg- D -Phe-Trp-NH 2 (SEQ. ID. NO: 6),

Phe- D -Arg-Lys-Trp-Tyr- D -Arg-His (SEQ. ID. NO: 7),

Gly- D -Phe-Lys-Tyr-His- D -Arg-Tyr-NH 2 (SEQ. ID. NO: 8),

Val- D -Lys-His-Tyr- D -Phe-Ser-Tyr-Arg-NH 2 (SEQ. ID. NO: 9),

Trp-Lys-Phe- D -Asp-Arg-Tyr- D -His-Lys (SEQ. ID. NO: 10),

Lys-Trp- D -Tyr-Arg-Asn-Phe-Tyr- D -His-NH 2 (SEQ. ID. NO: 11),

Thr-Gly-Tyr-Arg- D -His-Phe-Trp- D -His-Lys (SEQ. ID. NO: 12),

Asp- D -Trp-Lys-Tyr-D-His-Phe-Arg- D -Gly-Lys-NH 2 (SEQ. ID. NO: 13),

D -His-Lys-Tyr- D -Phe-Glu- D -Asp- D -His- D -Lys-Arg-Trp-NH 2 (SEQ. ID. NO: 14),

Ala- D -Phe- D -Arg-Tyr-Lys- D -Trp-His- D -Tyr-Gly-Phe (SEQ. ID. NO: 15),

Tyr- D -His-Phe- D -Arg-Asp-Lys- D -Arg-His-Trp- D -His-Phe (SEQ. ID. NO: 16),

Phe-Phe- D -Tyr-Arg-Glu-Asp- D -Lys-Arg- D -Arg-His-Phe-NH 2 (SEQ. ID. NO: 17),

Phe-Tyr-Lys- D -Arg-Trp-His- D -Lys- D -Lys-Glu-Arg- D -Tyr-Thr (SEQ. ID. NO: 18),

Tyr-Asp- D -Lys-Tyr-Phe- D -Lys- D -Arg-Phe-Pro- D -Tyr-His-Lys (SEQ. ID. NO: 19),

Glu-Arg- D -Lys-Tyr- D -Val-Phe- D -His-Trp-Arg- D -Gly-Tyr-Arg- D -Met-NH 2 (SEQ. ID. NO: 20),

Arg- D -Leu- D -Tyr-Phe-Lys-Glu- D -Lys-Arg- D -Trp-Lys- D -Phe-Tyr- D -Arg-Gly (SEQ. ID. NO: 21),

D -Glu-Asp-Lys- D -Arg- D -His-Phe-Phe- D -Val-Tyr-Arg-Tyr- D -Tyr-Arg-His-Phe-NH 2 (SEQ. ID. NO: 22),

Asp-Arg- D -Phe-Cys-Phe-D-Arg- D -Lys-Tyr-Arg- D -Tyr-Trp- D -His-Tyr- D -Phe-Lys-Phe (SEQ. ID. NO: 23),

His-Tyr- D -Arg-Trp-Lys-Phe- D -Asp-Ala-Arg-Cys- D -Tyr-His-Phe- D -Lys-Tyr-His-Ser-NH 2 (SEQ. ID. NO: 24),

Gly-Ala-Lys-Phe- D -Lys-Glu-Arg-Tyr-His- D -Arg- D -Arg-Asp-Tyr-Trp- D -His-Trp-His- D -Lys-Asp (SEQ. ID. NO: 25), or

Thr-Tyr-Arg- D -Lys-Trp-Tyr-Glu-Asp- D -Lys- D -Arg-His-Phe- D -Tyr-Gly-Val-Ile- D -His-Arg-Tyr-Lys-NH 2 (SEQ. ID. NO: 26).

31. A method of reducing the number of mitochondria undergoing mitochondrial permeability transitioning (MPT), or preventing mitochondrial permeability transitioning in a mammal in need thereof, the method comprising administering to the mammal an effective amount of a peptide having the formula

Lys- D -Arg-Tyr-NH 2 ,

Phe- D -Arg-His,

D -Tyr-Trp-Lys-NH 2 ,

Trp- D -Lys-Tyr-Arg-NH 2 ,

Tyr-His- D -Gly-Met,

Phe-Arg- D -His-Asp,

Tyr- D -Arg-Phe-Lys-Glu-NH 2 (SEQ. ID. NO: 3),

Met-Tyr- D -Lys-Phe-Arg (SEQ. ID. NO: 4),

D -His-Glu-Lys-Tyr- D -Phe-Arg (SEQ. ID. NO: 5),

Lys- D -Gln-Tyr-Arg- D -Phe-Trp-NH 2 (SEQ. ID. NO: 6),

Phe- D -Arg-Lys-Trp-Tyr- D -Arg-His (SEQ. ID. NO: 7),

Gly- D -Phe-Lys-Tyr-His- D -Arg-Tyr-NH 2 (SEQ. ID. NO: 8),

Val- D -Lys-His-Tyr- D -Phe-Ser-Tyr-Arg-NH 2 (SEQ. ID. NO: 9),

Trp-Lys-Phe- D -Asp-Arg-Tyr- D -His-Lys (SEQ. ID. NO: 10),

Lys-Trp- D -Tyr-Arg-Asn-Phe-Tyr- D -His-NH 2 (SEQ. ID. NO: 11),

Thr-Gly-Tyr-Arg- D -His-Phe-Trp- D -His-Lys (SEQ. ID. NO: 12),

Asp- D -Trp-Lys-Tyr-D-His-Phe-Arg- D -Gly-Lys-NH 2 (SEQ. ID. NO: 13),

D -His-Lys-Tyr- D -Phe-Glu- D -Asp- D -His- D -Lys-Arg-Trp-NH 2 (SEQ. ID. NO: 14),

Ala- D -Phe- D -Arg-Tyr-Lys- D -Trp-His- D -Tyr-Gly-Phe (SEQ. ID. NO: 15),

Tyr- D -His-Phe- D -Arg-Asp-Lys- D -Arg-His-Trp- D -His-Phe (SEQ. ID. NO: 16),

Phe-Phe- D -Tyr-Arg-Glu-Asp- D -Lys-Arg- D -Arg-His-Phe-NH 2 (SEQ. ID. NO: 17),

Phe-Tyr-Lys- D -Arg-Trp-His-D-Lys- D -Lys-Glu-Arg- D -Tyr-Thr (SEQ. ID. NO: 18),

Tyr-Asp- D -Lys-Tyr-Phe- D -Lys- D -Arg-Phe-Pro- D -Tyr-His-Lys (SEQ. ID. NO: 19),

Glu-Arg- D -Lys-Tyr- D -Val-Phe- D -His-Trp-Arg- D -Gly-Tyr-Arg- D -Met-NH 2 (SEQ. ID. NO: 20),

Arg- D -Leu- D -Tyr-Phe-Lys-Glu- D -Lys-Arg- D -Trp-Lys- D -Phe-Tyr- D -Arg-Gly (SEQ. ID. NO: 21),

D -Glu-Asp-Lys- D -Arg- D -His-Phe-Phe- D -Val-Tyr-Arg-Tyr- D -Tyr-Arg-His-Phe-NH 2 (SEQ. ID. NO: 22),

Asp-Arg- D -Phe-Cys-Phe-D-Arg- D -Lys-Tyr-Arg- D -Tyr-Trp- D -His-Tyr- D -Phe-Lys-Phe (SEQ. ID. NO: 23),

His-Tyr- D -Arg-Trp-Lys-Phe- D -Asp-Ala-Arg-Cys- D -Tyr-His-Phe- D -Lys-Tyr-His-Ser-NH 2 (SEQ. ID. NO: 24),

Gly-Ala-Lys-Phe- D -Lys-Glu-Arg-Tyr-His- D -Arg- D -Arg-Asp-Tyr-Trp- D -His-Trp-His- D -Lys-Asp (SEQ. ID. NO: 25), or

Thr-Tyr-Arg- D -Lys-Trp-Tyr-Glu-Asp- D -Lys- D -Arg-His-Phe- D -Tyr-Gly-Val-Ile- D -His-Arg-Tyr-Lys-NH 2 (SEQ. ID. NO: 26),

wherein the peptide is administered to the mammal as a composition comprising a pharmaceutically acceptable carrier.

32. A method of reducing the number of mitochondria undergoing mitochondrial permeability transitioning (MPT), or preventing mitochondrial permeability transitioning in a removed organ of a mammal, the method comprising administering to the removed organ an effective amount of a peptide having the formula

D-Arg-Dmt-Lys-Phe-NH 2 ,

D-Arg-Dmt-Phe-Lys-NH 2 ,

D-Arg-Phe-Lys-Dmt-NH 2 ,

D-Arg-Phe-Dmt-Lys-NH 2 ,

D-Arg-Lys-Dmt-Phe-NH 2 ,

D-Arg-Lys-Phe-Dmt-NH 2 ,

Phe-Lys-Dmt-D-Arg-NH 2 ,

Phe-Lys-D-Arg-Dmt-NH 2 ,

Phe-D-Arg-Dmt-Lys-NH 2 ,

Phe-D-Arg-Lys-Dmt-NH 2 ,

Phe-Dmt-D-Arg-Lys-NH 2 ,

Phe-Dmt-Lys-D-Arg-NH 2 ,

Lys-Phe-Dmt-D-Arg-NH 2 ,

Lys-Dmt-D-Arg-Phe-NH 2 ,

Lys-Dmt-Phe-D-Arg-NH 2 ,

Lys-D-Arg-Phe-Dmt-NH 2 ,

Lys-D-Arg-Dmt-Phe-NH 2 ,

D-Arg-Dmt-D-Arg-Phe-NH 2 ,

D-Arg-Dmt-D-Arg-Dmt-NH 2 ,

D-Arg-Dmt-D-Arg-Tyr-NH 2 ,

D-Arg-Dmt-D-Arg-Trp-NH 2 ,

Trp-D-Arg-Phe-Lys-NH 2 ,

Trp-D-Arg-Tyr-Lys-NH 2 ,

Trp-D-Arg-Trp-Lys-NH 2 ,

Trp-D-Arg-Dmt-Lys-NH 2 ,

D-Arg-Trp-Lys-Phe-NH 2 ,

D-Arg-Trp-Phe-Lys-NH 2 ,

D-Arg-Trp-Lys-Dmt-NH 2 ,

D-Arg-Trp-Dmt-Lys-NH 2 ,

D-Arg-Lys-Trp-Phe-NH 2 ,

D-Arg-Lys-Trp-Dmt-NH 2 ,

Cyclohexyl-D-Arg-Phe-Lys-NH 2 , or

Ala-D-Arg-Phe-Lys-NH 2 .

33. The method according to claim 32 , wherein the peptide has the formula D-Arg-Dmt-Lys-Phe-NH 2 .

34. A method of reducing the number of mitochondria undergoing mitochondrial permeability transitioning (MPT), or preventing mitochondrial permeability transitioning in a removed organ of a mammal, the method comprising administering to the removed organ an effective amount of a peptide having the formula

D-Arg-Dmt-Lys-Phe-NH 2 ,

D-Arg-Dmt-Phe-Lys-NH 2 ,

D-Arg-Phe-Lys-Dmt-NH 2 ,

D-Arg-Phe-Dmt-Lys-NH 2 ,

D-Arg-Lys-Dmt-Phe-NH 2 ,

D-Arg-Lys-Phe-Dmt-NH 2 ,

Phe-Lys-Dmt-D-Arg-NH 2 ,

Phe-Lys-D-Arg-Dmt-NH 2 ,

Phe-D-Arg-Dmt-Lys-NH 2 ,

Phe-D-Arg-Lys-Dmt-NH 2 ,

Phe-Dmt-D-Arg-Lys-NH 2 ,

Phe-Dmt-Lys-D-Arg-NH 2 ,

Lys-Phe-Dmt-D-Arg-NH 2 ,

Lys-Dmt-D-Arg-Phe-NH 2 ,

Lys-Dmt-Phe-D-Arg-NH 2 ,

Lys-D-Arg-Phe-Dmt-NH 2 ,

Lys-D-Arg-Dmt-Phe-NH 2 ,

D-Arg-Dmt-D-Arg-Phe-NH 2 ,

D-Arg-Dmt-D-Arg-Dmt-NH 2 ,

D-Arg-Dmt-D-Arg-Tyr-NH 2 ,

D-Arg-Dmt-D-Arg-Trp-NH 2 ,

Trp-D-Arg-Phe-Lys-NH 2 ,

Trp-D-Arg-Tyr-Lys-NH 2 ,

Trp-D-Arg-Trp-Lys-NH 2 ,

Trp-D-Arg-Dmt-Lys-NH 2 ,

D-Arg-Trp-Lys-Phe-NH 2 ,

D-Arg-Trp-Phe-Lys-NH 2 ,

D-Arg-Trp-Lys-Dmt-NH 2 ,

D-Arg-Trp-Dmt-Lys-NH 2 ,

D-Arg-Lys-Trp-Phe-NH 2 ,

D-Arg-Lys-Trp-Dmt-NH 2 ,

Cyclohexyl-D-Arg-Phe-Lys-NH 2 , or

Ala-D-Arg-Phe-Lys-NH 2 ,

wherein the peptide is administered to the removed organ as a composition comprising a pharmaceutically acceptable carrier.

35. The method according to claim 34 , wherein the peptide has the formula D-Arg-Dmt-Lys-Phe-NH 2 .

36. A method of reducing the number of mitochondria undergoing mitochondrial permeability transitioning (MPT), or preventing mitochondrial permeability transitioning in a removed organ of a mammal, the method comprising administering to the removed organ an effective amount of a peptide having the formula Phe-D-Arg-Phe-Lys-NH 2 or Dmp-D-Arg-Phe-Lys-NH 2 .

37. A method of reducing the number of mitochondria undergoing mitochondrial permeability transitioning (MPT), or preventing mitochondrial permeability transitioning in a removed organ of a mammal, the method comprising administering to the removed organ an effective amount of a peptide having the formula Phe-D-Arg-Phe-Lys-NH 2 or Dmp-D-Arg-Phe-Lys-NH 2 , wherein the peptide is administered to the removed organ as a composition comprising a pharmaceutically acceptable carrier.

38. A method of reducing the number of mitochondria undergoing mitochondrial permeability transitioning (MPT), or preventing mitochondrial permeability transitioning in a removed organ of a mammal, the method comprising administering to the removed organ an effective amount of a peptide having the formula

Lys- D -Arg-Tyr-NH 2 ,

Phe- D -Arg-His,

D -Tyr-Trp-Lys-NH 2 ,

Trp- D -Lys-Tyr-Arg-NH 2 ,

Tyr-His- D -Gly-Met,

Phe-Arg- D -His-Asp,

Tyr- D -Arg-Phe-Lys-Glu-NH 2 (SEQ. ID. NO: 3),

Met-Tyr- D -Lys-Phe-Arg (SEQ. ID. NO: 4),

D -His-Glu-Lys-Tyr- D -Phe-Arg (SEQ. ID. NO: 5),

Lys- D -Gln-Tyr-Arg- D -Phe-Trp-NH 2 (SEQ. ID. NO: 6),

Phe- D -Arg-Lys-Trp-Tyr- D -Arg-His (SEQ. ID. NO: 7),

Gly- D -Phe-Lys-Tyr-His- D -Arg-Tyr-NH 2 (SEQ. ID. NO: 8),

Val- D -Lys-His-Tyr- D -Phe-Ser-Tyr-Arg-NH 2 (SEQ. ID. NO: 9),

Trp-Lys-Phe- D -Asp-Arg-Tyr- D -His-Lys (SEQ. ID. NO: 10),

Lys-Trp- D -Tyr-Arg-Asn-Phe-Tyr- D -His-NH 2 (SEQ. ID. NO: 11),

Thr-Gly-Tyr-Arg- D -His-Phe-Trp- D -His-Lys (SEQ. ID. NO: 12),

Asp- D -Trp-Lys-Tyr- D -His-Phe-Arg- D -Gly-Lys-NH 2 (SEQ. ID. NO: 13),