Potent enhancement of [³H]nitrendipine binding in rat cerebral cortical and cardiac homogenates: A putative mechanism for the action of MDL 12,330A

[³H]Nitrendipine ([³H]NTD), a specific high-affinity calcium channel antagonist, was used to label dihydropyridine binding sites associated with calcium channels in rat cerebral cortical and cardiac homogenates. A novel lactamimide compound, MDL 12,33A, has been shown previously to have negative inotropic and chronotropic effects in isolated working guinea-pig hearts and these effects are reversed by the administration of calcium. MDL 12,330A is potent in enhancing [³H]NTD binding in membranes prepared from the cerebral cortex and the heart, with EC₅₀ values of 6.1 x 10^-8 and 3.4 x 10^-8M, respectively, at 37°C. This allosteric effect by MDL 12,330A is similar to that produced by a known calcium channel antagonist, d-cis diltiazem, which has been shown previously to enhance [³H]NTD binding at 37°C. The extent of enhancement by MDL 12,330A depends on incubation temperature (37°C>25°C>0°C). The mechanism of this enhancement by MDL 12,330A is due to a decrease in the dissociation rate constant of the dihydropyridine-calcium channel supramolecular complex. MDL 12,330A is the most potent drug thus far examined which demonstrates the enhancement of [³H]NTD binding.