CCK receptor antagonists.
1. The peptide hormone and neurotransmitter, cholecystokinin, is widely distributed throughout the gastrointestinal tract and central nervous system and mediates a diverse number of biological functions. 2. Two receptor subtypes, CCK-A and CCK-B, have been identified by both pharmacological characterization and molecular cloning. The CCK-A receptor is the predominant peripheral CCK receptor subtype and the CCK-B receptor is the predominant central CCK receptor. In addition, there are discrete populations of CCK-A receptors in the brain and CCK-B receptors are present in gastric mucosa. 3. Subtype selective antagonists have been developed which discriminate between the two receptor subtypes. One of the major chemical classes has exploited a benzodiazepine template present in asperlicin which was initially discovered in a natural product screen for CCK receptor antagonists. 4. The structurally related benzodiazepines L-365,260, L-740,093, and YM022 are selective antagonists of the CCK-B receptor subtype. Their in vitro pharmacological profiles have been characterized using the human CCK-B receptor expressed in CHO cells. 5. L-365,260 behaves in a manner consistent with that of a competitive antagonist and both L-740,093 and YM022 behave as insurmountable CCK-B receptor antagonists in vitro.
Dunlop
J
J
CNS Disorders, Wyeth-Ayerst Research, Princeton, NJ 08543, USA. Dunlopj@war.wyeth.com
D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology; D001570:Benzodiazepinones / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D006801:Humans; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors* / Q000145:classification / Q000502:physiology
D001570:Benzodiazepinones; D010671:Phenylurea Compounds; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines; C087260:YM 022; C090649:L 740093; C058121:L 365260