Controlled Modification of Acidity in Cholecystokinin B Receptor Antagonists:  N-(1,4-Benzodiazepin-3-yl)-N ‘-[3-(tetrazol-5-ylamino)phenyl]ureas

The design, synthesis, and biological activity of a novel series of CCK-B receptor antagonists (1) which incorporate a tetrazol-5-ylamino functionality attached to the phenyl ring of the arylurea moiety of L-365,260 are described. In these compounds, the acidity of the tetrazole was gradually modified by utilization of simple conformational constraints, and X-ray crystallographic data were obtained to support the conformational dependence of the pK_a of the aminotetrazoles. Compounds to emerge from the present work such as 1f and 2c,d are among the highest affinity and, in the case of 1f, most selective (CCK-A/CCK-B, 37 000) antagonists so far reported for this receptor. The C₅-cyclohexyl compound 2c (L-736,380) dose-dependently inhibited gastric acid secretion in anesthetized rats (ID₅₀, 0.064 mg/kg) and ex vivo binding of [¹²⁵I]CCK-8S in BKTO mice brain membranes (ED₅₀, 1.7 mg/kg) and is one of the most potent acidic CCK-B receptor antagonists yet described.