Cyclic polypeptides having mu-receptor specificity

• US 4,684,620 A
• Filed: 09/04/1984
• Issued: 08/04/1987
• Est. Priority Date: 09/04/1984
• Status: Expired due to Fees

• Current Assignee: Arizona Board of Regents (University of Arizona)
• Original Assignee: Gibson-Stephens Neuropharmaceuticals, Inc.
• Inventors: Pelton, John T., Hruby, Victor J.
• Primary Examiner(s): NOT, DEFINED
• Application Number:
  US06/647,184
• Time in Patent Office: 1,064 Days
• Field of Search: 260/112.55, 514/806, 514/11, 530/809, 530/329, 530/302
• US Class Current: 514/17.7
• 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: C07K 14/6555 at least 1 amino acid in D-form
• CPC Class Codes: Y10S 530/809 Fused cells, e.g. hybridoma
• CPC Class Codes: Y10S 930/16 Somatostatin; related peptides

Abstract

Novel compounds which are capable of binding with enhanced specificity to the mu opioid receptor are disclosed. The compounds are analogs of somatostain and have the formula: ##STR1## wherein X is CONH₂ or CH₂ OH;

Y and Z are independently sulfur or CH₂ ;

R¹ and R², which may be the same or different, are hydrogen, methyl, ethyl, cyclopentamethylene, or a lower alkyl group having five or less carbon atoms;

R³ and R⁴, which may be the same or different, are hydrogen, methyl, ethyl, cyclopentamethylene, or a lower alkyl group having five or less carbon atoms, provided, however, that R¹, R², R³, and R⁴ may not all be hydrogen;

AA₁ is Phe, D-Phe, phenyl-Gly, D-phenyl-Gly, Tyr, D-Tyr, L-1-Naphthylalanine, D-1-Naphthylalanine, or D-Phe(4-Me);

AA₂ is Tyr, Phe, Tyr(OMe), Phe(4-Me),

Tyr(OEt), or Phe(4-Et); and

AA₃ is Lys, Arg, Orn or homo-Arg.

The novel compounds have antagonist activity and may be used to induce pharmacological or therapeutic effects in humans and other animals.

Claims

1. A polypeptide having the formula:

##STR43## wherein X is CONH₂ or CH₂ OH;

Y and Z are independently sulfur or CH₂ ;

R¹ and R², which may be the same or different, are hydrogen, methyl, ethyl, cyclopentamethylene, or a lower alkyl group having five or less carbon atoms;

R³ and R⁴, which may be the same or different, are hydrogen, methyl, ethyl, cyclopentamethylene, or a lower alkyl group having five or less carbon atoms, provided, however, that R¹, R², R³, and R⁴ may not all be hydrogen;

AA₁ is Phe, D-Phe, phenyl-Gly, D-phenyl-Gly, Tyr, D-Tyr, L-1-Naphthylalanine, D-1-Naphthylalanine, or D-Phe(4-Me);

AA2 is Tyr, Phe, Tyr(OMe), Phe(4-Me),

Tyr(OEt), or Phe(4-Et); and

AA₃ is Lys, Arg, Orn or homo-Arg.

2. A polypeptide according to claim 1 having the formula:

##STR44##

3. A polypeptide according to claim 1 having the formula:

##STR45##

4. A polypeptide according to claim 1 having the formula:

##STR46##

5. A polypeptide according to claim 1 having the formula:

##STR47##

6. A polypeptide according to claim 1 having the formula:

##STR48##

7. A polypeptide according to claim 1 having the formula:

##STR49##

8. A polypeptide according to claim 1 having the formula:

##STR50##

9. A compound according to claim 1 wherein either R¹ and R² both methyl or R³ and R⁴ are both methyl.

10. A compound according to claim 1 wherein said compound is a mu receptor antagonist.

11. A process for treating irritable bowel disease comprising administering a safe and effective amount of an opioid receptor antagonist of claim 10.

12. A process for ameliorating opioid effects in humans and other mammals comprising administering a safe and effective amount of an opioid receptor compound of claim 1.

13. A process for treating digestive diseases in humans and other mammals comprising administering a safe and effective amount of an opioid receptor compound of claim 1.

14. The process of claim 12 wherein said opioid effects are opiate addiction, constipation or, respiratory depression.

15. A pharmaceutical composition comprising an effective amount of an opioid receptor antagonist having enhanced specificity for the mu opioid receptors of the formula:

##STR51## wherein X is CONH₂ or CH₂ OH;

Y and Z are independently sulfur or CH₂ ;

Rhu 1 and R², which may be the same or different, are hydrogen, methyl, ethyl, cyclopentamethylene, or a lower alkyl group having five or less carbon atoms;

R³ and R⁴, which may be the same or different, are hydrogen, methyl, ethyl, cyclopentamethylene, or a lower alkyl group having five or less carbon atoms, provided, however, that R¹, R², R³, and R⁴ may not all be hydrogen;

AA₁ is Phe, D-Phe, phenyl-Gly, D-phenyl-Gly, Tyr, D-Tyr, L-1-Naphthylalanine, D-1-Naphthylalanine, or D-Phe(4-Me);

AA₂ is Tyr, Phe, Tyr(OMe), Phe(4-Me),

Tyr(OEt), or Phe(4-Et); and

AA₃ is Lys, Arg, Orn or homo-Arg or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.

16. The pharmaceutical composition of claim 15 wherein Rl and R² are hydrogen and R³ and R⁴ are methyl.