Are anticonvulsants 'two thirds' of local anesthetics? A quantum pharmacology study

摘要

Local anesthetics and phenylureide anticonvulsants are both known to exert their pharmacologic effects y binding to the voltage-gated sodium ion channel, possibly at the same site. Given their similar modes of action, it was hypothesized that the two groups of drugs would be found to share similarities in the three-dimensional orientation of their shared chemical features (e.g. phenyl and carbonyl groups). To explore this possibility, density funcitonal calculations were used to find the minimum energy conformations of five anticonvulsants and seven local anesthetics. The distance between phenyl ring and carbonyl oxygen, two groups thought to participate in binding interactions at the sodium channel, was determined and compared for both classes of drug. The phenyl-carbonyl oxygen separation was found to be 4.2 ± 0.2 A for the anticonvulsants, while a similar value of 3.6 ± 0.4 A was obtained for the local anesthetics. Overlapping the minimized structures of one anticonvulsant and one local anesthetic confirmed this similarity. These findings suggest a comon motif for binding to the voltage-gated ion channel, leading us to propose that anticonvulsants are each 'two thirds' of a local anesthetic, having the characteristic phenyl and amide/ester groups of local anesthetics but lacking their terminal amine.