title: Characterization of the binding of [3H]SR 33805 to the slow Ca2+ channel in rat heart sarcolemmal membrane.
abstract: SR 33805 is a representative of a new class of compounds (indole sulfone) that inhibits L-type Ca2+ channels. [3H]SR 33805 has been shown to bind with a high affinity (Kd approximately 20 pM calculated from saturation isotherms and association/dissociation kinetics) to a single site in a purified preparation of rat cardiac sarcolemmal membranes. The binding was found to be saturable and reversible. The maximal binding capacity was in approximately 1:1 stoichiometry with that of other Ca2+ channel antagonists. Various cations (Na+, Ca2+, Cd2+, and La3+) were shown to inhibit specific [3H]SR 33805 binding, with La3+ being the most potent. Using a range of receptor or channel ligands (including omega-conotoxin and Na+ and K+ channel modulators), only the L-type Ca2+ channel antagonists were found to displace [3H]SR 33805. However, dihydropyridines, phenylalkylamines, benzothiazepines, and diphenyl-butylpiperidines were found to inhibit [3H]SR 33805 in a non-competitive manner as demonstrated by displacement experiments in addition to dissociation kinetics. In contrast, the interaction of SR 33805 with fantofarone has been found to be competitive. Binding of [3H]SR 33805 (and [3H]fantofarone) is entropy driven as opposed to that of the [3H]nitrendipine which is enthalpy driven. From these results we suggest that SR 33805 binds with a high affinity to a unique site on the L-type Ca2+ channel found in rat cardiac sarcolemmal membranes. This site is equivalent to that of fantofarone and in allosteric interaction with that of the dihydropyridines, phenylalkylamines and benzothiazepines.
authors.affiliation: Sanofi-Pharma Research Centre, Brussels, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Chatelain
authors.forename: P
authors.initials: P
authors.lastname: Dewinkeleer
authors.forename: P
authors.initials: P
authors.lastname: Beaufort
authors.forename: L
authors.initials: L
authors.lastname: Meysmans
authors.forename: M
authors.initials: M
authors.lastname: Clinet
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D002412:Cations / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D007212:Indolizines / Q000493:pharmacokinetics; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D009568:Nitrendipine / Q000493:pharmacokinetics; D010627:Phenethylamines / Q000493:pharmacokinetics; D051381:Rats; D012508:Sarcolemma / Q000378:metabolism*; D013450:Sulfones / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002412:Cations; D007211:Indoles; D007212:Indolizines; D010627:Phenethylamines; D013450:Sulfones; C084255:SR 33805; D009568:Nitrendipine; C059901:fantofarone