DISCOVERY OF 1,5-BENZODIAZEPINES WITH PERIPHERAL CHOLECYSTOKININ (CCK-A) RECEPTOR AGONIST ACTIVITY .1. OPTIMIZATION OF THE AGONIST TRIGGER

Directed screening of compounds selected from the Glare registry file for contractile activity on the isolated guinea pig gallbladder (GPGB) identified a series of 1,5-benzodiazepines with peripheral cholecysto kinin (CCK) receptor agonist activity. Agonist efficacy within this se ries was modulated by variation of substituents on the N1-anilinoaceta mide moiety. Remarkably, a single methyl group confers agonist activit y, with an N-isopropyl substituent providing optimal efficacy. Hydroph ilic substituents on the anilino nitrogen abolish agonist activity or produce antagonists of CCK. In contrast, hydrophilic electron-donating groups at the para-position of the anilino ring enhance or maintain i n vitro and in vivo agonist activity. Despite decreased affinity for t he human CCK-A receptor, relative to CCK-8, some of these compounds ar e equipotent to CCK as anorectic agents in rats following intraperiton eal administration.