EFFECTS OF 2 CHEMICALLY RELATED NEW CA2-TYPE CARDIAC CHANNEL( CHANNELANTAGONISTS, SR33557 (FANTOFARONE) AND SR33805, ON THE L)

Fantofarone (SR33557) is a substituted indolizine and SR33805 is a sub stituted indole. These drugs have been shown to specifically bind to t he alpha(1) subunit of the L-type Ca2+ channel at the same site, disti nct from those of the classical 1,4-dihydropyridine, phenylalkylamine or benzothiazepine Ca2+ antagonists, but in negative allosteric intera ction with them. The present work shows that fantofarone and SR33805 b lock L-type but not T-type Ca2+ channels in mouse cardiac cells in pri mary 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 EC(50) = 1.4 and 4.1 nM, respect ively. In polarized conditions (i.e. at a holding potential of -80 mV) , SR33805 is a better Ca2+ channel blocker (EC(50) = 33 nM) than fanto farone (EC(50) = 0.15 mu M). Therefore differences in their chemical s tructures make the blacking action of fantofarone more sensitive to vo ltage than that of SR33805.