title: alpha-adrenergic antagonists as possible calcium channel inhibitors.
abstract: The effects of various organic Ca2+ channel inhibitors were investigated on the binding of the alpha 1-antagonist 3H-labeled 2-[(2',6'-dimethoxyphenoxyethyl)aminomethyl]-1,4-benzodioxane ([3H]WB-4101) to membranes from rat brain and neuroblastoma-glioma hybrid cells (NG108-15). As found by monitoring binding of [3H]WB-41-1, the Ca2+ channel inhibitors methoxyverapamil (D600), verapamil, and the nifedipine analogue YC-93 bind to two different sites in rat brain: a high-affinity site (dissociation constant Kd = 2.9 nM and binding capacity B = 360 fmol/mg of protein) and a low-affinity site (Kd = 260 nM and B = 2700 fmol/mg of protein). In NG108-15 cells, where no alpha 1 receptors were detected with [3H]WB-4101, the Ca2+ antagonists were found to bind to nonadrenergic sites in the membrane with a capacity B = 976 fmol/mg of protein. The binding of Ca2+ antagonists to [3H]WB-41-1 sites led to the investigation of WB-4101 as a Ca2+ inhibitor by electrophysiological techniques. WB-4101 depressed the amplitude and reduced the rate of rise of the CA2+ spike with an affinity slightly greater than that observed for D600. The concentration for 50% inhibition of the Ca2+ spike amplitude was 48 microM for WB-4101 and 80 microM for D600. The WB-4101-induced blockade of the Ca2+ spike was antagonized by high Ca2+ concentrations, indicating a common site for Ca2+ and the alpha-antagonist. D600 and WB-4101 also inhibited voltage-dependent Na+ and K+ conductances. The results suggest that Ca2+ channels can account for a fraction of the sites labeled with [3H]WB-4101 in membrane preparations from brain and NG108-15 cells.
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004146:Dioxanes / Q000378:metabolism / Q000494:pharmacology*; D004147:Dioxins / Q000494:pharmacology*; D005711:Gallopamil / Q000494:pharmacology; D005910:Glioma; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009447:Neuroblastoma; D051381:Rats; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D004147:Dioxins; D007473:Ion Channels; D005711:Gallopamil; D014700:Verapamil; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; D002118:Calcium