CCK peptides with combined features of hexa- and tetrapeptide CCK-A agonists

J Med Chem. 2000 Jun 15;43(12):2350-5. doi: 10.1021/jm990252e.

Abstract

Selective CCK-A agonist activity has been reported to induce satiety in a variety of animals, including man, and thereby suggests a therapeutic role for CCK in the management of obesity. To date, three general classes of CCK-A agonists have been reported, the full-length, sulfated hepta- and hexapeptides, a series of tetrapeptides, and most recently a series of benzodiazepines. The SAR of the hexa- and tetrapeptide classes suggests that the Hpa(SO(3)H) and Tac groups may not interact at the CCK-A receptor in the same location. However, the C-terminal dipeptide part of the hexapeptides and tetrapeptides appear to interact at the CCK-A receptor in a similar manner. Compound 7 (Hpa-Nle-Gly-Trp-Lys(Tac)-Asp-MePhe-NH(2)) derived from combining the features of the hexapeptides and the tetrapeptides has subnanomolar affinity and 3500-fold selectivity for CCK-A receptors. Compound 7 administered intraperitoneally produces potent, long-lasting reduction in food intake in rats and a corresponding weight loss when administered over nine consecutive days.

MeSH terms

  • Animals
  • Appetite Depressants / chemical synthesis
  • Appetite Depressants / chemistry
  • Appetite Depressants / metabolism
  • Appetite Depressants / pharmacology
  • Binding, Competitive
  • Body Weight / drug effects
  • Cerebral Cortex / metabolism
  • Eating / drug effects
  • In Vitro Techniques
  • Male
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / metabolism
  • Oligopeptides / pharmacology
  • Pancreas / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Cholecystokinin A
  • Receptors, Cholecystokinin / agonists*
  • Structure-Activity Relationship
  • Synaptosomes / metabolism

Substances

  • 4-hydroxyphenylacetyl-norleucyl-glycyl-tryptophyl-lysyl((((4-methylphenyl)sulfonyl)amino)carbonyl)-aspartyl-N-methylphenylalaninamide
  • Appetite Depressants
  • Oligopeptides
  • Receptor, Cholecystokinin A
  • Receptors, Cholecystokinin