The dihydropyridine (DHP) Ca2+ channel blocking drugs nicardipine, nitrendipine, nimodipine, felodipine, nifedipine and nisoldipine were examined for activity in inhibiting specific (-)-[3H]QNB and [3H] WB4101 binding to the muscarinic and α-adrenergic receptors, respectively, of rat brain. Muscarinic receptor binding was affected most by nicardipine, with felodipine having less activity; the other DHP drugs were essentially inactive at 3 × 10-5 M. The (+)-stereoisomer of nicardipine (Kl = 4.07 × 10-7 M) was 27 times more potent than the (-)-isomer in inhibiting [3H]QNB binding, and this inhibition was found to be competitive. This inhibitory effect of nicardipine was not mediated via interaction with the high-affinity DHP binding site assumed to be associated with a Ca2+ channel. (+)-Nicardipine inhibited the binding of [3H]nitrendipine to this DHP binding site of brain, with a Kl of 9.01 × 10-11 M, and was 10 times more potent than the (-)-isomer. Thus, the muscarinic receptor was 4200 times less sensitive to (+)-nicardipine than was this DHP binding site. Nicardipine was also the most potent DHP drug inhibiting [3H]WB4104 binding to the α-adrenergic receptor, although the other drugs were also somewhat active, in the rank order sequence listed above. This effect of nicardipine on the adrenergic receptor was also stereoselective, with (+)-nicardipine (Kl = 3.46 × 10-7 M) being about 3 times more potent than the (-)-isomer, in producing competitive inhibition of radioligand binding. These data suggest that the effects on brain receptors occur as a result of direct, stereospecific effects of DHP drugs on these receptors and are not due to Ca2+ channel blocking activity of these drugs.
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Acknowledgemenfs-This work was supported by PHS GrantH L30761-01b.y Hoffmann-LaRochIen,c ., andt he U.S. Air Force of Scientific Research Contract F4962G