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.
Romey
G
G
Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Valbonne, France.
Bois
P
P
Lazdunski
M
M
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D004558:Electric Stimulation; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D007211:Indoles / Q000494:pharmacology*; D007212:Indolizines / Q000494:pharmacology*; D051379:Mice; D010627:Phenethylamines / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D007211:Indoles; D007212:Indolizines; D010627:Phenethylamines; D013450:Sulfones; C084255:SR 33805; C059901:fantofarone