Effects of a new class of calcium antagonists, SR33557 (fantofarone) and SR33805, on neuronal voltage-activated Ca++ channels.
SR33557 (fantofarone) and SR33805 are structurally novel calcium antagonists that bind selectively to the alpha 1-subunit of the L-type Ca++ channel at a site distinct from the classical 1,4-dihydrophyridine, phenylalkylamine and benzothiazepine sites but in allosteric interactions with them. Blocking effects of fantofarone and SR33805 on the different types of voltage-activated Ca++ currents have been investigated with the whole-cell patch-clamp method in chick dorsal root ganglion neurons (for T-, L- and N-type currents) and in rat cerebellar Purkinje neurons (for P-type current) in primary culture. Neuronal L-type Ca++ channels are blocked totally by fantofarone and SR33805 in the microM range of concentration as in skeletal muscle and cardiac cells at a holding membrane potential of -80 mV. The sequence of efficacy is SR33805 (IC50 = 26 nM) > fantofarone (IC50 = 0.35 microM). N- and P-type channels are not very sensitive to fanto-farone and SR33805 (IC50 approximately 5 microM). The T-type channel is not affected by these drugs.
Romey
G
G
Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France.
Lazdunski
M
M
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D002478:Cells, Cultured; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D007212:Indolizines / Q000494:pharmacology*; D010627:Phenethylamines / Q000494:pharmacology*; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013450:Sulfones / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007211:Indoles; D007212:Indolizines; D010627:Phenethylamines; D013450:Sulfones; C084255:SR 33805; C059901:fantofarone