BIOLOGICAL PROPERTIES OF THE BENZODIAZEPINE AMIDINE DERIVATIVE L-740,093, A CHOLECYSTOKININ-B GASTRIN RECEPTOR ANTAGONIST WITH HIGH-AFFINITY IN-VITRO AND HIGH POTENCY IN-VIVO

A novel series of 5-amino-1,4-benzodiazepin-2-one derivatives (amidine s), which contain a cationic solubilizing group and which are antagoni sts for the cholecystokinin (CCK)-B receptor, have been identified. Op timization of this series led to the identification of an azabicyclono nane amidine, L-740,093 -1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)ur ea], that bound with high affinity to CCK-B receptors from guinea pig cerebral cortex (IC50 of 0.1 nM) and had a CCK-B/CCK-A receptor select ivity of 16,000. in comparison, L-365,260 had 85-fold lower affinity ( 8.5 nM) and was only 87-fold selective for CCK-B over CCK-A receptors. L-740,093 bound with high affinity to guinea pig gastrin receptors in vitro (IC50 of 0.04 nM). Electrophysiological studies on slices of ra t ventromedial hypothalamic nucleus showed that L-740,093 produced rig htward shifts of the concentration-response curve for the CCK-B recept or agonist pentagastrin (K-b of 0.06 nM). L-740,093 blocked pentagastr in-induced gastric acid secretion in anesthetized rats with a 50% inhi bitory dose of 0.01 mg/kg, intraperitoneally, showing 100-fold greater activity, compared with L-365,260 (50% inhibitory dose of 1 mg/kg, in traperitoneally). An ex vivo binding assay in mice was used to investi gate the interaction of L-740,093 with central CCK binding sites. Afte r intravenous administration, L-740,093 inhibited ex vivo binding dose dependently, with a 50% effective dose of 0.2 mg/kg. These studies de monstrate that L-740,093 is the most potent and selective CCK-B antago nist yet described and that it has excellent central nervous system pe netration.