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We investigated the antagonistic activity of (R)-1-[2,3-dihydro-1-(2'- methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3- (3-methylphenyl) urea (YM022), a benzodiazepine derivative, at CCKB/gastrin receptors. This compound potently inhibited [125I]CCK-8 binding to rat brain CCKB/gastrin receptors with a Ki value of 0.26 nM, but it showed weak affinity for rat pancreas CCKA receptors (Ki = 270 nM). Selectivity for CCKB/gastrin receptors was 1000-fold greater than that for CCKA receptors. Changes in intracellular free Ca2+ concentration ([Ca2+]i) in response to CCK-8 were measured in a rat anterior pituitary cell line GH3 by fura-2 fluorometry. CCK-8 (1-100 nM) dose-dependently increased [Ca2+]i in these cells, whereas YM022 had no effect on baseline [Ca2+]i even at the highest concentration of 100 nM. YM022 inhibited the mobilization of [Ca2+]i elicited by 10 nM CCK-8 in a concentration-dependent manner with an IC50 value of 4 nM. In conclusion, YM022 is an extremely potent and highly selective antagonist of CCKB/gastrin receptors. This compound is therefore useful for studying the physiological and pharmacological roles of CCKB/gastrin receptors.
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