CONTROLLED MODIFICATION OF ACIDITY IN CHOLECYSTOKININ B RECEPTOR ANTAGONISTS - ZEPIN-3-YL)-N'-[3-(TETRAZOL-5-YLAMINO)PHENYL]UREAS

The design, synthesis, and biological activity of a novel series of CC K-B receptor antagonists (1) which incorporate a tetrazol-5-ylamino fu nctionality attached to the phenyl ring of the arylurea moiety of L-36 5,260 are described. In these compounds, the acidity of the tetrazole was gradually modified by utilization of simple conformational constra ints, and X-ray crystallographic data were obtained to support the con formational dependence of the pK(a) of the aminotetrazoles. Compounds to emerge from the present work such as 1f and 2c,d are among the high est affinity and, in the case of 1f, most selective (CCK-A/CCK-B, 37 0 00) antagonists so far reported for this receptor. The C-5-cyclohexyl compound 2c (L-736,380) dose-dependently inhibited gastric acid secret ion in anesthetized rats (ID50, 0.064 mg/kg) and er vivo binding of [I -125]CCK-8S in BKTO mice brain membranes (ED(50), 1.7 mg/kg) and is on e of the most potent acidic CCK-B receptor antagonists yet described.