YM022 1H-1,4-BENZODIAZEPIN-3-YL]-3-(3-METHYLPHENYL)UREA] - AN IRREVERSIBLE CHOLECYSTOKININ TYPE-B RECEPTOR ANTAGONIST

A functional evaluation of the recently developed cholecystokinin type -B (CCK-B) receptor antagonist YM022 2-H-1,4-benzodiazepin-3-yl]-3(3-m ethylphenyl)urea] was undertaken in Chinese hamster ovary cells stably expressing the human CCK-B receptor gene (hCCK-B.CHO). YM022 exhibite d high affinity and selectivity for the CCK-B receptor subtype as esti mated from [I-125]CCK8S displacement studies using membranes derived f rom hCCK-B.CHO and hCCK-A.CHO cells. Functional antagonist activity of YMO22 was demonstrated employing CCK-4-stimulated Ca2+ mobilization i n hCCK-B.CHO cells. In the presence of 30 nM YM022, the maximum effect of CCK-4 was suppressed to 48 +/- 11% of control, an effect that was accompanied by a modest rightward shift in the CCK-4 concentration-res ponse curve. In contrast, the structurally similar CCK-B receptor anta gonist L-365,260[3R(+)-N[2,3-dihydro-1 -1H-1,4-benzodiazepin-3-yl]-N'- (methylphenyl)urea; 30 nM-10 mu M] produced progressive rightward shif ts in the CCK-4 concentration-response curve, with no effect observed on the CCK-4 maximum response. Further characterization using the tech nique of microphysiometry revealed that the agonist activity of CCK-4 was not restored following washout after exposure to YM022. The antago nist activity of L-365,260, however, was found to be fully reversible in this system. Thus, YM022 behaves as an irreversible antagonist, whi lst its structural analogue L-365,260 exhibits properties consistent w ith a competitive antagonist. (C) 1997 Elsevier Science Inc.