Selective antagonism of calcium channel activators by fluspirilene

1 Fluspirilene has been claimed to bind to a high affinity site in the calcium channel in skeletal muscle. We have investigated its calcium‐antagonistic effects in smooth muscle and affinity for the channel in radioligand binding assays. 2 Fluspirilene was weakly active as an antagonist of Ca 2+ ‐induced contractions in K + ‐depolarized taenia preparations from the guinea‐pig caecum, with threshold antagonism starting from concentrations of 30 n m . Nitrendipine, nicardipine and nimodipine were very potent antagonists in this model (threshold antagonism, > 1 n m ). 3 In contrast, fluspirilene (10–1000 n m ) was a potent non‐competitive antagonist of the effects of Bay K 8644 (1–3000 n m ) on Ca 2+ ‐induced contractions and, at 10 n m , selectively antagonised the effects of Bay K 8644, abolished the Ca 2+ ‐channel activator effects of CGP 28392, without changing the calcium antagonist effects of nitrendipine, or modifying the sensitivity of the tissues to Ca 2+ . In contrast, the dihydropyridines were more effective as antagonists of Ca 2+ than of Bay K 8644. Fluspirilene therefore selectively antagonised the effects of dihydropyridine Ca 2+ channel activators without affecting the antagonist potency. 4 In radioligand binding experiments, fluspirilene was a potent displacer of [ 3 H]‐PN‐200‐110 binding to rat cerebral cortical membranes (EC 50 30 n m ), albeit with a low Hill slope (0.66), and was more potent than other lipophilic diphenylalkylamines such as flunarizine and lidoflazine. Fluspirilene interacted non‐competitively with [ 3 H]‐PN‐200‐110 and increased dissociation of the radioligand.