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

Selective CCK-A agonist activity has been reported to induce satiety in a v ariety of animals, including man, and thereby suggests a therapeutic role f or CCK in the management of obesity. To date, three general classes of CCK- A agonists have been reported, the full-length, sulfated hepta- and hexapep tides, a series of tetrapeptides, and most recently a series of benzodiazep ines. The SAR of the hexa- and tetrapeptide classes suggests that the Hpa(S O3H) and Tac groups may not interact at the CCK-A receptor in the same loca tion. However, the C-terminal dipeptide part of the hexapeptides and tetrap eptides appear to interact at the CCK-A receptor in a similar manner. Compo und 7 (Hpa-Nle-Gly-Trp-Lys(Tac)-Asp-MePhe-NH2) derived from combining the f eatures of the hexapeptides and the tetrapeptides has subnanomolar affinity and 3500-fold selectivity for CCK-A receptors. Compound 7 administered int raperitoneally produces potent, long-lasting reduction in food intake in ra ts and a corresponding weight loss when administered over nine consecutive days.