Receptor binding properties of the new calcium antagonist benidipine hydrochloride

The in vitro receptor binding affinity of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-diyhydropyridine-3, 5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) to 3H-nitrendipine, alpha 1-adrenergic, alpha 2-adrenergic, beta-adrenergic, muscarinic cholinergic, H1-histaminergic, D2-dopaminergic, S2-serotonergic, A1 adenosine and A2 adenosine receptors was compared with that of nifedipine, nitrendipine and nicardipine. KW-3049 bound stereospecifically to 3H-nitrendipine binding sites of rat myocardium with high affinity (Ki = 0.13 nmol/l) and to the rat brain alpha 1-receptor (Ki = 1.2 mumol/l). KW-3049 exhibited no remarkable binding affinity to alpha 2, beta-, D2-, H1-, S2-, A1-, A2- and muscarinic cholinergic receptors at 100 mumol/l. KW-3049 showed competitive inhibition against 3H-nitrendipine binding when it was added simultaneously with the ligand and rat heart membranes. KW-3049 did not affect the dissociation of 3H-nitrendipine from the receptor sites. The inhibitory activity of various isomers of KW-3049 at the 3H-nitrendipine binding sites was shown in the order of S-S-(+) greater than KW-3049 (racemate, S-S-(+), R-R-(-] greater than R-R-(-) greater than S-R-(-) greater than racemate (R-S-(+), S-R-(-] greater than R-S-(+). S-S-(+)isomer was 12 times more potent than R-R-(-)isomer on Ki basis, whereas alpha 1-adrenoceptors followed the order of S-S-(+), R-S-(+), KW-3049, racemate (R-S-(+), S-R-(-], S-R-(-) and R-R-(-).