Nitrosylated neuropeptides

• US 5,612,314 A
• Filed: 04/21/1995
• Issued: 03/18/1997
• Est. Priority Date: 04/21/1995
• Status: Expired due to Fees

• Current Assignee: Brigham and Women's Hospital Incorporated, Trustees of Boston University
• Original Assignee: Brigham and Women's Hospital Incorporated, Trustees of Boston University
• Inventors: de Tejada, Inigo S., Stamler, Jonathan
• Primary Examiner(s): Cain, Edward J.
• Application Number:
  US08/426,935
• Time in Patent Office: 697 Days
• Field of Search: 514/13, 530/324, 530/325, 530/326, 530/327, 530/328, 530/329, 524/14, 524/15, 524/16, 524/17
• US Class Current: 514/1.7
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 14/57563 Vasoactive intestinal peptide [VIP]; Related peptides

Abstract

Neuropeptides, particularly vasoactive intestinal peptide(VIP) and fragments, mutations and derivatives thereof that have corresponding activities to which have been directly or indirectly linked at least one NO or NO₂ group, and their uses, including the relaxation of smooth muscle in several tissues, including vascular smooth muscle (e.g., aorta) and nonvascular smooth muscle (e.g. trachea, sphincter of Oddi, gastrointestinal smooth muscle and corpus cavernosum smooth muscle), and particularly also for the diagnosis and treatment of human male impotence.

Claims

1. A compound comprising a neuropeptide or analog, fragment or derivative thereof having vascular or non-vascular smooth muscle relaxant activity to which has been directly or indirectly linked at least one NO or NO₂ group.

2. The compound of claim 1 wherein the neuropeptide is selected from the group consisting of peptide histidine isoleucine, peptide histidine methionine, substance P, calcitonin gene-related peptide and a tachykinin.

3. The compound of claim 1 which comprises vasoactive intestinal peptide conjugated with a nitric oxide or nitric oxide-releasing moiety.

4. The compound of claim 3 which has the structure vasoactive intestinal peptide-glycine-cysteine-NO.

5. The compound of claim 1 which is a fragment of vasoactive intestinal peptide selected from the group consisting of those having peptides 1-6, 18-28, 15-28, 14-28 and 7-28 of the vasoactive intestinal peptide.

6. The compound of claim 1 which is a vasoactive intestinal peptide analog selected from the group consisting of the analog in which amino acid 11 is serine, the analog wherein amino acid 13 is phenylalanine, the analog wherein amino acid 26 is valine and the analog wherein amino acid 28 is threonine.

7. The compound of claim 1 which is a vasoactive intestinal peptide fragment having amino acids 11 to 23 thereof.

8. The compound of claim 1 which is a vasoactive intestinal peptide fragment having amino acids 15-20 thereof.

9. A composition comprising the compound of claim 1 in a pharmaceutically acceptable carrier.

10. A composition comprising the compound of claim 3 in a pharmaceutically acceptable carrier.

11. A method for relaxing vascular smooth muscle which comprises contacting said vascular smooth muscle with a vascular smooth muscle relaxing amount of the compound of claim 1.

12. A method for relaxing vascular smooth muscle which comprises contacting said vascular smooth muscle with a vascular smooth muscle relaxing amount of the compound of claim 3.

13. A method for the treatment of disease states responsive to the prevention or relaxation of undesirable contractions of vascular smooth muscle which comprises administering a vascular smooth muscle relaxing amount of the composition of claim 9 to an individual in need thereof.

14. A method for the treatment of disease states responsive to the prevention or relaxation of undesirable contractions of vascular smooth muscle which comprises administering a vascular smooth muscle relaxing amount of the composition of claim 10 to an individual in need thereof.

15. A method for preventing or treating vascular disorders involving vascular smooth muscle contraction which comprises administering to an individual in need thereof an amount of the composition of claim 9 effective to prevent or treat vascular disorders involving vascular smooth muscle contraction.

16. A method for preventing or treating vascular disorders involving vascular smooth muscle contraction which comprises administering to an individual in need thereof an amount of the composition of claim 10 effective to prevent or treat vascular disorders involving vascular smooth muscle contraction.

17. A method for relaxing non-vascular smooth muscle which comprises contacting said non-vascular smooth muscle with a non-vascular smooth muscle relaxing amount of the compound of claim 1.

18. A method for relaxing non-vascular smooth muscle which comprises contacting said non-vascular smooth muscle with a non-vascular smooth muscle relaxing amount of the compound of claim 1.

19. A method for the treatment of disease states responsive to the prevention or relaxation of undesirable contractions of non-vascular smooth muscle which comprises administering a non-vascular smooth muscle relaxing amount of the composition of claim 9 to an individual in need thereof.

20. A method for the treatment of disease states responsive to the prevention or relaxation of undesirable contractions of non-vascular smooth muscle which comprises administering a non-vascular smooth muscle relaxing amount of the composition of claim 10 to an individual in need thereof.

21. A method for relaxing airway smooth muscle which comprises contacting said airway smooth muscle with an airway smooth muscle relaxing amount of the compound of claim 1.

22. A method for relaxing airway smooth muscle which comprises contacting said airway smooth muscle with an airway smooth muscle relaxing amount of the compound of claim 3.

23. A method for the treatment of disease states responsive to the prevention or relaxation of undesirable contractions of airway smooth muscle which comprises administering an airway smooth muscle relaxing amount of the composition of claim 9 to an individual in need thereof.

24. A method for the treatment of disease states responsive to the prevention or relaxation of undesirable contractions of airway smooth muscle which comprises administering an airway smooth muscle relaxing amount of the composition of claim 10 to an individual in need thereof.

25. A method for preventing or treating an obstructive lung disorder selected from the group consisting of emphysema, asthma, bronchitis, fibrosis, excessive mucous secretion, obstruction of air flow and post-surgical complications which comprises administering to an individual in need thereof an amount effective to prevent or treat an obstructive lung disorder selected from the group consisting of emphysema, asthma, bronchitis, fibrosis, excessive mucous secretion, obstruction of air flow and post-surgical complications of the composition of claim 9.

26. A method for preventing or treating an obstructive lung disorder selected from the group consisting of emphysema, asthma, bronchitis, fibrosis, excessive mucous secretion, obstruction of air flow and post-surgical complications which comprises administering to an individual in need thereof an amount effective to prevent or treat an obstructive lung disorder selected from the group consisting of emphysema, asthma, bronchitis, fibrosis, excessive mucous secretion, obstruction of air flow and post-surgical complications of the composition of claim 10.

27. A method for relaxing gastrointestinal smooth muscle which comprises contacting said gastrointestinal smooth muscle with a gastrointestinal smooth muscle relaxing amount of the compound of claim 1.

28. A method for relaxing gastrointestinal smooth muscle which comprises contacting said gastrointestinal smooth muscle with a gastrointestinal smooth muscle relaxing amount of the compound of claim 3.

29. A method for the treatment of disease states responsive to the prevention or relaxation of undesirable contractions of gastrointestinal smooth muscle which comprises administering a gastrointestinal smooth muscle relaxing amount of the composition of claim 9 to an individual in need thereof.

30. A method for the treatment of disease states responsive to the prevention or relaxation of undesirable contractions of gastrointestinal smooth muscle which comprises administering a gastrointestinal smooth muscle relaxing amount of the composition of claim 10 to an individual in need thereof.

31. A method for preventing or treating gastrointestinal smooth muscle contractions or spasms associated with an endoscopic procedure which comprises administering to an individual in need thereof an amount effective to prevent or treat gastrointestinal smooth muscle contractions or spasms associated with an endoscopic procedure of the composition of claim 9.

32. A method for preventing or treating gastrointestinal smooth muscle contractions or spasms associated with an endoscopic procedure which comprises administering to an individual in need thereof an amount effective to prevent or treat gastrointestinal smooth muscle contractions or spasms associated with an endoscopic procedure of the composition of claim 10.

33. A method for relaxing corpus cavernosum smooth muscle which comprises contacting said corpus cavernosum smooth muscle with a corpus cavernosum smooth muscle relaxing amount of the compound of claim 1.

34. A method for relaxing corpus cavernosum smooth muscle which comprises contacting said corpus cavernosum smooth muscle with a corpus cavernosum smooth muscle relaxing amount of the compound of claim 3.

35. A method for the treatment of disease states responsive to the prevention or relaxation of undesirable contractions of corpus cavernosum smooth muscle which comprises administering a corpus cavernosum smooth muscle relaxing amount of the composition of claim 9 to an individual in need thereof.

36. A method for the treatment of disease states responsive to the prevention or relaxation of undesirable contractions of corpus cavernosum smooth muscle which comprises administering a corpus cavernosum smooth muscle relaxing amount of the composition of claim 10 to an individual in need thereof.

37. A method for preventing or treating human male impotence which comprises administering to a human male in need thereof an amount effective to prevent or treat human male impotence of the composition of claim 9.

38. A method for preventing or treating human male impotence which comprises administering to a human male in need thereof an amount effective to prevent or treat human male impotence of the composition of claim 10.

39. The method of claim 38 wherein administration is parenteral.

40. The method of claim 39 wherein administration is by injection into the corpus cavernosum, intraurethral catheterization or by topical administration.

41. The method of claim 38 wherein the vasoactive intestinal peptide is administered in a range from about 1 nM to 1 mM per kilogram of body weight.