RECEPTOR OCCUPATION AND PHARMACOKINETICS OF MPC-1304, A NEW CA2+ CHANNEL ANTAGONIST, IN SPONTANEOUSLY HYPERTENSIVE RATS

MPC-1304, (+/-)-methyl 2-oxopropyl imethyl-4-(2-nitrophenyl)-3,5-pyrid inedicarbonate, is a novel 1,4-dihydropyridine Ca2+ channel antagonist with potent and long lasting antihypertensive effects. We characteriz ed the ex vivo and in vivo binding properties of MPC-1304 to Ca2+ chan nel antagonist receptors in myocardial, aortic and brain tissues of sp ontaneously hypertensive rats (SHR) by radioreceptor assay using [H-3] (+)-PN 200-110 ([5-methyl-H-3](+)-PN 200-110 (4-(2,1,3-benzoxadia zol- 4-yl)-1,4-dihydro-5-methoxycarbonyl-2, 4-dihydro-3-isopropylcarbonylpy ridine-5-carboxylic acid methyl ester)). At 1 and 6 h after oral admin istration of MPC-1304 (10 mg/kg) in SHR, there was a significant decre ase (48%) in the number of [H-3](+)-PN 200-110 binding sites (B-max) i n myocardial membranes compared to control values. The plasma concentr ation of MPC-1304 in SHR correlated significantly with the occupation by this drug of myocardial Ca2+ channel antagonist receptors. The in v ivo specific binding of [H-3](+)-PN 200-110 in particulate fractions o f aorta of SHR was significantly reduced (74.8 and 37.9%, respectively ) at 1 and 6 h after oral administration of MPC-1304 (3 mg/kg), while the myocardial [H-3](+)-PN 200-110 binding was decreased only at 1 h l ater. In these rats, there was little change in cerebral cortical [H-3 ](+)-PN 200-110 binding. In conclusion, MPC-1304 exerted more selectiv e and sustained occupation in vivo of Ca2+ channel antagonist receptor s in vascular tissues of SHR than in those of myocardial and brain tis sues.