Effects of two chemically related new Ca2+ channel antagonists, SR33557 (fantofarone) and SR33805, on the L-type cardiac channel

Fantofarone (SR33557) is a substituted indolizine and SR33805 is a substituted indole. These drugs have been shown to specifically bind to the alpha 1 subunit of the L-type Ca2+ channel at the same site, distinct from those of the classical 1,4-dihydropyridine, phenylalkylamine or benzothiazepine Ca2+ antagonists, but in negative allosteric interaction with them. The present work shows that fantofarone and SR33805 block L-type but not T-type Ca2+ channels in mouse cardiac cells in primary culture. This block is voltage-dependent. Fantofarone and SR33805 are potent Ca2+ channel blockers in depolarized conditions (i.e. at a holding potential of -40 mV) with an EC50 = 1.4 and 4.1 nM, respectively. In polarized conditions (i.e. at a holding potential of -80 mV), SR33805 is a better Ca2+ channel blocker (EC50 = 33 nM) than fantofarone (EC50 = 0.15 microM). Therefore differences in their chemical structures make the blocking action of fantofarone more sensitive to voltage than that of SR33805.