title: Cholecystokinin antagonists: (R)-tryptophan-based hybrid antagonists of high affinity and selectivity for CCK-A receptors.
abstract: The intriguing structural similarities of glutamic acid based cholecystokinin (CCK) antagonists (A-64718 and A-65186) and the benzodiazepine CCK antagonist MK-329 (L-364,718) have been reported. Efforts to include the weak CCK antagonist benzotript into this construct utilizing a similar approach have resulted in a novel series of benzotript-based hybrid antagonists N alpha-(3'-quinolylcarbonyl)-(R)-tryptophan di-n-pentylamide (9, A-67396), N alpha-(4',8'-dihydroxy-2'-quinolylcarbonyl)-(R)-tryptophan di-n-pentylamide (23, A-70276), and N alpha-(3'-quinolylcarbonyl)-(R)-5'-hydroxytryptophan di-n-pentylamide (36, A-71134) which possess respectively binding affinities of 23, 21, and 11 nM for the pancreatic CCK-A receptor and which inhibit CCK8-induced amylase secretion. Compound 9 possesses a selectivity of greater than 500-fold for the pancreatic CCK-A receptor over the CCK-B receptor.
authors.affiliation: Neuroscience Research Division, Abbott Laboratories, Abbott Park, Illinois 60064.
authors.forename: J F
authors.initials: JF
authors.lastname: Kerwin
authors.forename: F
authors.initials: F
authors.lastname: Wagenaar
authors.forename: H
authors.initials: H
authors.lastname: Kopecka
authors.forename: C W
authors.initials: CW
authors.lastname: Lin
authors.forename: T
authors.initials: T
authors.lastname: Miller
authors.forename: D
authors.initials: D
authors.lastname: Witte
authors.forename: M
authors.initials: M
authors.lastname: Stashko
authors.forename: A M
authors.initials: AM
authors.lastname: Nadzan
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D001667:Binding, Competitive; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D005971:Glutamates / Q000138:chemical synthesis / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D011949:Receptors, Cholecystokinin / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D001549:Benzamides; D005971:Glutamates; D011949:Receptors, Cholecystokinin; D014364:Tryptophan; D002766:Cholecystokinin; C013841:benzotript