title: Potent enhancement of [3H]nitrendipine binding in rat cerebral cortical and cardiac homogenates: a putative mechanism for the action of MDL 12,330A.
abstract: [3H]Nitrendipine [( 3H]NTD), a specific high-affinity calcium channel antagonist, was used to label dihydropyridine binding sites associated with calcium channels in rat cerebral cortical and cardiac homogenates. A novel lactamimide compound, MDL 12,330A, has been shown previously to have negative inotropic and chronotropic effects in isolated working guinea-pig hearts and these effects are reversed by the administration of calcium. MDL 12,330A is potent in enhancing [3H]NTD binding in membranes prepared from the cerebral cortex and the heart, with EC50 values of 6.1 X 10(-8) and 3.4 X 10(-8) M, respectively, at 37 degrees C. This allosteric effect by MDL 12,330A is similar to that produced by a known calcium channel antagonist, d-cis diltiazem, which has been shown previously to enhance [3H]NTD binding at 37 degrees C. The extent of enhancement by MDL 12,330A depends on incubation temperature (37 degrees C greater than 25 degrees C greater than 0 degrees C). The mechanism of this enhancement by MDL 12,330A is due to a decrease in the dissociation rate constant of the dihydropyridine-calcium channel supramolecular complex. MDL 12,330A is the most potent drug thus far examined which demonstrates the enhancement of [3H]NTD binding.
authors.forename: H R
authors.initials: HR
authors.lastname: Lee
authors.forename: J A
authors.initials: JA
authors.lastname: Jaros
authors.forename: W R
authors.initials: WR
authors.lastname: Roeske
authors.forename: N L
authors.initials: NL
authors.lastname: Wiech
authors.forename: R
authors.initials: R
authors.lastname: Ursillo
authors.forename: H I
authors.initials: HI
authors.lastname: Yamamura
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D006207:Half-Life; D006321:Heart / Q000187:drug effects; D007097:Imines / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000378:metabolism; D009568:Nitrendipine; D051381:Rats; D011919:Rats, Inbred Strains; D013696:Temperature; D014316:Tritium
chemical_list: D002121:Calcium Channel Blockers; D007097:Imines; D014316:Tritium; C014925:RMI 12330A; D009568:Nitrendipine; D009543:Nifedipine