Receptor occupation and pharmacokinetics of MPC-1304, a new Ca2+ channel antagonist, in spontaneously hypertensive rats

MPC-1304, (+/-)-methyl 2-oxopropyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarbonate , is a novel 1,4-dihydropyridine Ca2+ channel antagonist with potent and long-lasting antihypertensive effects. We characterized the ex vivo and in vivo binding properties of MPC-1304 to Ca2+ channel antagonist receptors in myocardial, aortic and brain tissues of spontaneously hypertensive rats (SHR) by radioreceptor assay using [3H](+)-PN 200-110 ([5-methyl-3H](+)-PN 200-110 (4-(2,1,3-benzoxadiazol-4-yl)-1,4,-dihydro-5-methoxycarbonyl-2,6-d imethyl-1,4-dihydro-3-isopropylcarbonylpyridine-5-carboxylic acid methyl ester)). At 1 and 6 h after oral administration of MPC-1304 (10 mg/kg) in SHR, there was significant decrease (48%) in the number of [3H](+)-PN 200-110 binding sites (Bmax) in myocardial membranes compared to control values. The plasma concentration of MPC-1304 in SHR correlated significantly with the occupation by this drug of myocardial Ca2+ channel antagonist receptors. The in vivo specific binding of [3H](+)-PN 200-110 in particulate fractions of aorta of SHR was significantly reduced (74.8 and 37.9%, respectively) at 1 and 6 after oral administration of MPC-1304 (3 mg/kg), while the myocardial [3H](+)-PN 200-110 binding was decreased only at 1 h later. In these rats, there was little change in cerebral cortical [3H](+)-PN 200-110 binding. In conclusion, MPC-1304 exerted more selective and sustained occupation in vivo of Ca2+ channel antagonist receptors in vascular tissues of SHR than in those of myocardial and brain tissues.