Calcium entry blocking activities of MPC-1304 and of its enantiomers and metabolites.
The Ca2+ entry blocking effects of MPC-1304, a new Ca2+ entry blocker of the 1,4-dihydropyridine type, and of its (S) and (R) enantiomers and metabolites were examined on Ca(2+)-induced contractions in isolated rabbit arteries. The Ca2+ entry blocking activity of the (S) enantiomer of MPC-1304 was approximately 150 times greater than that of its (R) enantiomer. Likewise, the antihypertensive effect of the (S) enantiomer was twice as great as that of MPC-1304 (racemate) in conscious spontaneously hypertensive rats, while the (R) enantiomer was ineffective. Thus, most of the pharmacological activity of MPC-1304 resides in its (S) configuration. The main metabolic products of MPC-1304 also inhibited the Ca(2+)-induced contraction in the isolated vascular smooth muscles. These active metabolites showed a stereoselectivity similar to that of MPC-1304 for Ca2+ entry blocking activity, and may contribute to the potent antihypertensive action of MPC-1304.
Okumura
K
K
New Drug Research Laboratory, Maruko Pharmaceutical Co., Ltd., Kasugai, Japan.
Ichihara
K
K
Nagasaka
M
M
Oda
N
N
Tajima
K
K
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D004095:Dihydropyridines / Q000378:metabolism / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D013237:Stereoisomerism
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C059427:aranidipine; D002118:Calcium