title: SR 33557, a novel calcium-antagonist: interaction with [3H]-(+/-)-nitrendipine and [3H]-(-)-desmethoxy-verapamil binding sites in cerebral membranes.
abstract: We investigated the pharmacological properties of SR 33557, a novel compound with calcium-antagonist properties, in both functional tests in vitro and radioligand binding studies. SR 33557 potently antagonized calcium-induced contraction of potassium-depolarized rat aorta in vitro with an IC50 value of 5.6 +/- 0.9 nM, but was a much weaker inhibitor of noradrenaline-induced contraction of the same tissue (IC50 = 96 +/- 22 nM). SR 33557 totally inhibited [3H]-(+/-)-nitrendipine binding to rat brain membranes with a Ki value of 0.19 +/- 0.03 nM. Diltiazem, which used alone increases [3H]-(+/-)-nitrendipine binding, reversed this inhibition indicating that SR 33557 allosterically regulates [3H]-(+/-)-nitrendipine binding. SR 33557 also fully inhibited [3H]-(-)-desmethoxyverapamil binding to cerebral membranes, but inhibition curves were biphasic. IC50 value calculated for that part of the curve which reflects the high affinity binding site of SR 33557 (IC50 = 0.20 +/- 0.02 nM) was very similar to the Ki value determined for inhibition of [3H]-(+/-)-nitrendipine binding. Kinetic evidences indicate that SR 33557 binds to a site which is distinct from the 1,4-dihydropyridine or the phenylalkylamine binding sites associated with the calcium channel. To test the pharmacological specificity of these interactions, the ability of SR 33557 to interact with eight other receptors in cerebral or heart membranes was assessed by binding assays. No high-affinity interaction was observed between SR 33557 and any of the receptors investigated. We conclude that SR 33557 binds specifically and with a high affinity to a site closely associated with the voltage-operated calcium channel in cerebral membranes.
authors.affiliation: Sanofi, Sanofi-Labaz Research Center, Brussels, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Nokin
authors.forename: M
authors.initials: M
authors.lastname: Clinet
authors.forename: P
authors.initials: P
authors.lastname: Polster
authors.forename: P
authors.initials: P
authors.lastname: Beaufort
authors.forename: L
authors.initials: L
authors.lastname: Meysmans
authors.forename: J
authors.initials: J
authors.lastname: Gougat
authors.forename: P
authors.initials: P
authors.lastname: Chatelain
mesh_terms: D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D015220:Calcium Channels; D004110:Diltiazem / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007212:Indolizines / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D009568:Nitrendipine / Q000378:metabolism*; D010627:Phenethylamines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011978:Receptors, Nicotinic / Q000378:metabolism*; D014700:Verapamil / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007212:Indolizines; D010627:Phenethylamines; D011978:Receptors, Nicotinic; C043184:4-desmethoxyverapamil; D009568:Nitrendipine; D014700:Verapamil; D004110:Diltiazem; C059901:fantofarone