Stereoselective and nonstereoselective inhibition exhibited by the enantiomers of verapamil

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Abstract
The interaction of the isomers of verapamil with sites on the calcium channel and α1-adrenergic receptor has been examined. The inhibitory potency of these enantiomers differ with respect to the agonist. KCl- or clonidine-induced contractions of rabbit aortic rings were inhibited in a stereoselective manner by the enantiomers of verapamil with the (−)-isomer being more potent than the (+)-isomer. Similarly, (−)-verapamil was also more potent at displacing (−)-[N-methyl-3H]desmethoxyverapamil than was the (+)-isomer. In contrast, the inhibition of norepinephrine- or phenylephrine-induced aortic contractions was not stereoselective. Differences in enantiomer potency were also observed in vivo. The ability of clonidine to increase blood pressure in the anesthetized rat was blocked in a stereoselective manner by the verapamil enantiomers, while inhibition of the pressor actions of phenylephrine was not. In summary, for agents that rely heavily on calcium channel function (KCl, clonidine), stereoselective inhibition was observed. Stereoselective inhibition was not observed against high efficacy α1-agonists. This difference in stereochemistry argues that verapamil does not act at the same site when inhibiting clonidine or KCl action when compared with norepinephrine or phenylephrine.Key words: calcium channels, phenylalkylamines, α-receptors, vascular smooth muscle, stereochemistry.