CP-060 S interacts with three principal binding sites on the L-type Ca 2+ channel

Abstract

CP-060 S, (−)-( S)-2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-[3-[ N-methyl- N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]-1,3-thiazolidin-4-one hydrogen fumarate is a novel cardioprotective drug, which is able to prevent Na +-, Ca 2+-overload and also has Ca 2+ channel blocking activity. The latter action of CP-060 S was characterized by radioligand binding experiments with rat cardiac membranes in terms of the interaction with the three principal binding sites on the L-type Ca 2+ channel, which bind such drugs as the 1,4-dihydropyridines, phenylalkylamines and benzothiazepines. CP-060 S exhibited complete and concentration-dependent inhibition of [ 3 H ](+)-PN200-110, [ 3 H ](−)-desmethoxyverapamil and [ 3 H ]cis-(+)-diltiazem binding to their specific binding sites. Saturation studies showed that CP-060 S increased the K d of [ 3 H ](+)-PN200-110 and [ 3 H ](−)-desmethoxyverapamil without causing a significant change in the maximum binding density. The dissociation kinetics of the three radioligands were accelerated by CP-060 S. These results suggest that CP-060 S interacts with a novel binding site on the L-type Ca 2+ channel and has a negative allosteric interaction with the three principal binding sites for the 1,4-dihydropyridines, phenylalkylamines and benzothiazepines.