Structural dependency of the inhibitory action of benzodiazepines and related compounds on the mitochondrial Na+-Ca2+ exchanger.

Na+-induced Ca2+-release from guinea-pig heart mitochondria is inhibited by benzodiazepines such as clonazepam (compound II, IC50: 12 microM). The capacity of various related compounds to inhibit the rapid Ca2+-efflux induced by 20 mM Na+ was examined. The potency of inhibition was found to depend on several factors, such as a 2'-halogen substitution and the presence of a secondary amido group. Very effective inhibitors were identified among the triazolo derivatives of benzodiazepines or obtained by replacing the diazepine ring by an oxazepine or a thiazepine. Some of these favourable structural modifications were compounded in the benzothiazepine 7-chloro-3,5-dihydro-5-phenyl-1H-4,1-benzothiazepine-2-on (compound XVI), which proved to be about 20 times more potent than the related compounds clonazepam and diltiazem. Compound XVI, which has an IC50 in the submicromolar range, is the most potent selective inhibitor of the mitochondrial exchanger so far reported. The structural requirements found for the inhibition of the mitochondrial Na+-Ca2+ exchanger were quite distinct from those described for the binding of benzodiazepines to their central-type and peripheral-type sites.