A New Ca-Antagonist, CD-349, Binding to the Ca-Channel of Rat Myocardium and Brain and Hog Coronary Artery

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Abstract
The binding to a Ca-channel of a novel 1,4-dihydropyridine (DHP) Caantagonist, 2-nitratopropyl 3-nitratopropyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (CD-349), was studied in rat myocardium and brain and hog coronary artery, and the binding was compared with that of other DHPs. In rat myocardium, the binding reaction of [3H]CD-349 was faster than that of nitrendipine (NTD). The association rate constant of [3H]CD-349 was about 10 times higher than that of [3H]NTD. The dissociation rate was also higher than that of [3H]NTD. Scatchard plot analysis of [3H]CD-349 binding showed one high affinity site for CD-349. The dissociation constant (Kd) and maximum number of binding sites (Bmax) were 333 pM and 286 fmoles/mg protein. They were almost the same as those for [3H]NTD. [3H]CD-349 and [3H]NTD bindings were dose dependently inhibited by 1,4-DHPs: nifedipine, nimodipine, nicardipine and CD-349. The order of the inhibitory potency of these drugs was CD-349> nicardipine > nimodipine> nifedipine, when [3H]CD-349 and [3H] NTD were used as the ligands. Similar results were obtained for rat brain and hog coronary artery. [3H]CD-349 binding was not changed by .alpha.- or .beta.-adrenergic, cholinergic, histaminergic or serotonergic agents in rat myocardium. From these results, it is suggested that CD-349 binds to the Ca-channel reversibly with high affinity due to its high association rate for the site.

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