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 hexapep...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2000-06, Vol.43 (12), p.2350-2355
Main Authors: Pierson, M. Edward, Comstock, Jeanne M, Simmons, Roy D, Julien, Ronald, Kaiser, Frederick, Rosamond, James D
Format: Article
Language:English
Subjects:
Animals
Appetite Depressants - chemical synthesis
Appetite Depressants - chemistry
Appetite Depressants - metabolism
Appetite Depressants - pharmacology
Binding, Competitive
Biological and medical sciences
Body Weight - drug effects
Cerebral Cortex - metabolism
Eating - drug effects
In Vitro Techniques
Male
Medical sciences
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Oligopeptides - chemical synthesis
Oligopeptides - chemistry
Oligopeptides - metabolism
Oligopeptides - pharmacology
Pancreas - metabolism
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Rats
Rats, Sprague-Dawley
Receptor, Cholecystokinin A
Receptors, Cholecystokinin - agonists
Structure-Activity Relationship
Synaptosomes - metabolism
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Summary: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(SO3H) 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-NH2) 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm990252e