1-Benzazepin-2-one calcium channel blockers--VI. Receptor-binding model and possible relationship to desmethoxyverapamil.

We have prepared a series of potent antihypertensive 1-benzazepin-2-one calcium channel blockers (CCBs) 1 that are structurally related to diltiazem 2. Structural studies and the preparation of conformationally constrained analogs of 1-benzazepin-2-ones have led us to postulate a receptor-bound conformation for both 1 and 2. We believe that these compounds bind to the calcium channel protein in an MI ("inboard") binding conformation in which the amine of the side chain is placed over the heptagonal benzazepione ring and in close proximity to the phenyl methyl ether pharmacophore. This receptor-bound conformation places the side chain amine and methyl ether pharmacophores in the same spatial relationship as 3-methoxyphenylethalamine. Combined with our SAR, this binding model rationalizes literature findings that desmethoxyverapamil can demonstrate pharmacology typical of both phenylalkylamine (PA) and benzothiazepinone (DTZ) calcium channel blockers. Simple experiments are proposed to test the hypothesis that desmethoxyverapamil can bind at the benzothiazepinone site on the calcium channel.