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 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.
Pierson
M E
ME
AstraZeneca R&D Boston, Three Biotech, One Innovation Drive, Worcester, Massachusetts 01605, USA.
Comstock
J M
JM
Simmons
R D
RD
Julien
R
R
Kaiser
F
F
Rosamond
J D
JD
D000818:Animals; D001067:Appetite Depressants / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D001835:Body Weight / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010179:Pancreas / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin / Q000819:agonists*; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism
C410933:4-hydroxyphenylacetyl-norleucyl-glycyl-tryptophyl-lysyl((((4-methylphenyl)sulfonyl)amino)carbonyl)-aspartyl-N-methylphenylalaninamide; D001067:Appetite Depressants; D009842:Oligopeptides; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin