Binding properties of (+/-)[3H]benidipine hydrochloride to rat heart membranes.
Benidipine is a newly developed slow-onset and long-lasting dihydropyridine calcium antagonist. The kinetics of specific binding of (+/-)[3H]benidipine to the dihydropyridine receptor sites in rat heart membranes were assessed. The dissociation constant (Kd) and the maximal number of binding sites were 0.078 +/- 0.029 nM and 286 +/- 6 fmol/mg of protein, respectively. Association and dissociation rate constants of (+/-)[3H]benidipine binding were 4 and 50 times smaller, respectively, than those of (+/-)[3H]nitrendipine binding. In displacement studies, the decreasing order of potency was benidipine, nisoldipine, nicardipine, nitrendipine, nifedipine, and Bay K 8644. A high stereoselectivity was observed, with Ki values of 0.028 nM in the S-S-(+) isomer and 4.4 nM in the R-R-(-) isomer of this drug. Benidipine had a high affinity for specific binding, with an inhibition constant of 0.084 nM, which was in good agreement with the Kd value stated above. Among the stimulants and blockers of alpha- and beta-adrenergic, cholinergic, histaminergic, dopaminergic, serotonergic, or GABAergic receptors, no drug inhibited or enhanced specific (+/-)[3H]benidipine binding. These binding properties of (+/-)[3H]benidipine may explain its unique slow onset and long-lasting antihypertensive activities.
Ishii
A
A
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co. Ltd., Nagoya, Japan.
Toyama
J
J
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000378:metabolism* / Q000493:pharmacokinetics; D004095:Dihydropyridines / Q000378:metabolism* / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D009568:Nitrendipine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C061004:benidipine; D009568:Nitrendipine