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Interactions of calmodulin antagonists with calcium antagonists binding sites

1991; Elsevier BV; Volume: 206; Issue: 4 Linguagem: Inglês

10.1016/0922-4106(91)90117-z

1872-8251

Paul Schaeffer, Claire Lugnier, Jean‐Claude Stoclet,

Phenothiazines and Benzothiazines Synthesis and Activities

Calmodulin antagonists have calcium entry blocking properties. In order to quantitatively investigate the interactions of these drugs with calcium channels, their effect on [3H]nitrendipine and [3H]d-cis-diltiazem binding to rat cerebral cortex membrane preparations was compared to their inhibitory effect on the activation of cyclic nucleotide phosphodiesterase by calmodulin. The potency of most antagonists to inhibit [3H]nitrendipine binding was correlated with their calmodulin inhibitory potency. However, bepridil (K0.5 = 280 nM), chlorpromazine (K0.5 = 3 μM), triflupromazine (K0.5 = 1.5 μM), imipramine (K0.5 = 3 μM) and propranolol (K0.5 = 14 μM) were much more active on [3H]d-cis-diltiazem binding than on either [3H]nitrendipine binding or calmodulin, suggesting that these compounds bind to higher affinity sites on the calcium antagonist target proitein. Moreover, the potencies of these compounds to compete with [3H]d-cis-diltiazem and to inhibit calcium-induced contractions in depolarized smooth muscle were correlated (R = 0.76, p < 0.02). These data suggest that love concentrations of these hydrophobic drugs which have calcium and calmodulin antagonistic properties inhibit smooth muscle contraction through calcium entry blockade, not calmodulin antagonism.