title: CP-060S interacts with three principal binding sites on the L-type Ca2+ channel.
abstract: CP-060S, (-)-(S)-2-[3,5-bis(1,1-dimethylethyl)-4-hydroxypheny1]-3-[3-[N-met hyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]-1,3-thi azolidin-4-one hydrogen fumarate is a novel cardioprotective drug, which is able to prevent Na+-, Ca2+-overload and also has Ca2+ channel blocking activity. The latter action of CP-060S 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 Ca2+ channel, which bind such drugs as the 1,4-dihydropyridines, phenylalkylamines and benzothiazepines. CP-060S exhibited complete and concentration-dependent inhibition of [3H](+)-PN200-110, [3H](-)-desmethoxyverapamil and [3H]cis-(+)-diltiazem binding to their specific binding sites. Saturation studies showed that CP-060S increased the Kd of [3H](+)-PN200-110 and [3H](-)-desmethoxyverapamil without causing a significant change in the maximum binding density. The dissociation kinetics of the three radioligands were accelerated by CP-060S. These results suggest that CP-060S interacts with a novel binding site on the L-type Ca2+ channel and has a negative allosteric interaction with the three principal binding sites for the 1,4-dihydropyridines, phenylalkylamines and benzothiazepines.
authors.affiliation: Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., Shizuoka, Japan. suzukiysy@gt.chugai-pharm.co.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Suzuki
authors.forename: K
authors.initials: K
authors.lastname: Tamura
authors.forename: Y
authors.initials: Y
authors.lastname: Adachi
authors.forename: M
authors.initials: M
authors.lastname: Fukazawa
authors.forename: T
authors.initials: T
authors.lastname: Kato
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D004095:Dihydropyridines / Q000378:metabolism / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology*; D053778:Thiazolidines
chemical_list: C104781:CP 060S; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D013844:Thiazoles; D053778:Thiazolidines