title: Effects of dihydropyridine calcium channel blocking drugs on rat brain muscarinic and alpha-adrenergic receptors.
abstract: 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 alpha-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 X 10(-5) M. The (+)-stereoisomer nicardipine (KI = 4.07 X 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 K1 of 9.01 X 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 alpha-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 (KI = 3.46 X 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.
authors.forename: S A
authors.initials: SA
authors.lastname: Thayer
authors.forename: M
authors.initials: M
authors.lastname: Welcome
authors.forename: A
authors.initials: A
authors.lastname: Chhabra
authors.forename: A S
authors.initials: AS
authors.lastname: Fairhurst
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels; D004095:Dihydropyridines; D004146:Dioxanes / Q000378:metabolism; D005711:Gallopamil / Q000494:pharmacology; D066298:In Vitro Techniques; D009529:Nicardipine; D009543:Nifedipine / Q000031:analogs & derivatives / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D011976:Receptors, Muscarinic / Q000187:drug effects*; D011978:Receptors, Nicotinic / Q000032:analysis; D013237:Stereoisomerism
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D004146:Dioxanes; D011725:Pyridines; D011942:Receptors, Adrenergic, alpha; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D005711:Gallopamil; D011813:Quinuclidinyl Benzilate; C038806:1,4-dihydropyridine; D009529:Nicardipine; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; D009543:Nifedipine