Slow dissociation of the new slow-onset and long-acting calcium antagonist benidipine hydrochloride from 3H-nitrendipine binding sites.
The dissociation rates of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarb oxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) and some calcium antagonists from 3H-nitrendipine binding sites were studied by a centrifugation technique and a filter-absorbed tissue method. KW-3049 dissociated from 3H-nitrendipine binding sites more slowly than other calcium antagonist, namely nifedipine, nitrendipine, nilvadipine, nicardipine and nisoldipine. The slow dissociation of KW-3049 from 3H-nitrendipine binding sites was supported by the equilibrium binding studies. When KW-3049 was preincubated with rat cardiac membrane, its inhibitory potency was enhanced 2.6-fold, whereas nifedipine did not alter its potency. In ex vivo binding, following administration of KW-3049 to rat, 3H-nitrendipine binding site was occupied in a dose-dependent manner and this occupation returned to a control level after 24 h. These results of receptor binding studies are in agreement with the pharmacological characteristics of KW-3049.
Ishii
A
A
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Nishida
K
K
Oka
T
T
Nakamizo
N
N
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002121:Calcium Channel Blockers / Q000378:metabolism*; D008297:Male; D009529:Nicardipine / Q000378:metabolism; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000378:metabolism; D015737:Nisoldipine; D009568:Nitrendipine / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D002121:Calcium Channel Blockers; C035100:nilvadipine; C050883:benidipine hydrochloride; D015737:Nisoldipine; D009568:Nitrendipine; D009529:Nicardipine; D009543:Nifedipine