PHARMACOLOGICAL PROFILE OF -1H-1,4-BENZODIAZEPIN-3-YL]-3-(3-METHYLPHENYL)UREA (YM022), A NEW POTENT AND SELECTIVE GASTRIN CHOLECYSTOKININ-BRECEPTOR ANTAGONIST, IN-VITRO AND IN-VIVO

yl-1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)ur (YM022) is an extre mely potent and highly selective gastrin/cholecystokinin (CCK)-B recep tor antagonist. We compared the gastrin/CCK-B receptor-blocking proper ties of this compound with those of the racemate (mixture of YM022 and its S-form), its enantiomer (S-form), L-365,260 and Cl-988 in vitro a nd in vivo. YM022 replaced specific binding of [I-125]CCK-8 to rat bra in gastrin/CCK-B receptors in a stereoselective and competitive manner . The K-i value of YM022 for gastrin/CCK-B receptors in brain were est imated to be 0.068 nM. The racemate, the S-form of YM022, L-365,260 an d Cl-988 also replaced gastrin/CCK-B receptor binding, with K-i values of 0.11, 140, 19 and 6.3 nM, respectively. The affinity of YM022 for gastrin/CCK-B receptor was more than 2 orders of magnitude higher than that for rat pancreatic CCK-A receptor and various other receptors, s uch as benzodiazepine. In vivo, intravenous (i.v.) administration of Y M022 inhibited pentagastrin-induced gastric acid secretion in anesthet ized rats, with an ED(50) value of 0.0078 mu mol/kg. Inhibition by the S-form of YM022 was only 33.8% even at the relatively high dose of 1 mu mol/kg i.v. L-365,260 (1-10 mu mol/kg i.v.) and Cl-988 (0.3-3 mu mo l/kg i.v.) also antagonized acid secretion induced by pentagastrin, wi th ED(50) values of 4.23 and 1.01 mu mol/kg, respectively. YM022 (10 m u mol/ kg) and Cl-988 (30 mu mol/kg) did not affect histamine- and bet hanechol-induced acid secretion in anesthetized rats, whereas L-365,26 0 (3-30 mu mol/kg) inhibited acid secretion induced by these secretago gues in a dose-dependent fashion. These results suggest that YM022 is an extremely potent and highly selective gastrin/CCK-B receptor antago nist.