Differential properties of the optical-isomers of pranidipine, a 1,4-dihydropyridine calcium channel modulator.
Pranidipine is an optically-active 1,4-dihydropyridine (DHP) voltage-dependent L-type calcium channel inhibitor. Certain enantiomeric pairs display opposite effects, i.e., inhibition and activation of the calcium channel while others exhibit the same qualitative actions. We investigated pranidipine, a new DHP, using a paradigm of vascular smooth muscle reactivity. In isolated rat aorta, depolarized with 80 mM KCl, both isomers of pranidipine caused a right-ward shift of the concentration-contraction curves for extracellular Ca2+. The apparent pA2, values of the S-isomer and R-isomer were 10.03 and 8.36, respectively, providing evidence that the calcium channel blocking action of the S-isomer was 50 times more potent than that of the R-isomer. Antihypertensive actions of these two isomers studied in pentobarbital-anaesthetized spontaneously hypertensive rats, revealed that the S-isomer, at doses of 3-30 microg/kg i.v. decreased blood pressure in a dose-dependent manner, while the R-isomer had no effect on blood pressure at those doses. We conclude that the pair of enantiomers of pranidipine qualitatively display the same Ca2+ channel blocking action and that neither isomer exhibits Bay K 8644-like activation. Pranidipine may be useful in studies on the architecture of the DHP receptor 'pocket'.
Hirano
T
T
2nd Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan.
Mori
T
T
Kido
M
M
Toide
K
K
Ohura
M
M
Fujiki
H
H
Orito
K
K
Yoshida
K
K
Ikezono
K
K
Sumida
T
T
Nakayama
N
N
Yabuuchi
Y
Y
D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001011:Aorta; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D004095:Dihydropyridines / Q000494:pharmacology* / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C048161:pranidipine