Effects of dihydropyridine calcium channel blocking drugs on rat brain muscarinic and α-adrenergic receptors

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 (K_l = 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 K_l 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 (K_l = 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.