Pharmacological evaluation of new calcium antagonists: 2-substituted 3-dimethylamino-5,6-methylenedioxyindenes.

Calcium antagonists are valuable pharmacological tools for the study of stimulussecretion and excitation-contraction coupling mechanisms. Two 2-substituted 3-dimethylamino-5,6-methylenedioxyindene hydrochlorides were tested for antagonism of the spasmogenic action of various agonists on isolated smooth muscle preparations. The 2-n-propyl and 2-n-butyl aminoindenes (5 X 10(-5) to 10(-4) M) blocked the spasmogenic action on the estrogen-treated rat uterus of prostaglandin E2 (10(-7) M), prostaglandin F2alpha tromethamine salt (10(-7) M), oxytocin (10(-3) U/ml), barium chloride (BaCl2-2H2O; 2.2 X 10(-4) M), acetylcholine chloride (10(-6) M) and ergonovine maleate (7.5 X 10(-4) M); they also blocked the contractile effect on the ileum of acetylcholine chloride (10(-6) M; rat) and histamine hydrochloride (10(-6) M; guinea pig). In further experiments on rat uterus using the agonists acetylcholine chloride (10(-6) M; which presumably acts by increasing influx of extracellular calcium into cells) and barium chloride (2.2 X 10(-4) M; which presumably contracts smooth muscle by releasing intracellular calcium), a progressive increase in extracellular calcium concentration (from 9 X 10(-4) to 7.2 X 10(-3) M CaCl2-2H2O) was paralleled by progressive reversal of the blockade produced by both 2-substituted aminoindene antagonists. In studies on the perfused bovine adrenal medulla, the 2-n-propyl aminoindene (10(-4) M) completely blocked the calcium-dependent catecholamine secretion evoked by 0.1 and 3.3 mM carbachol, without affecting the calcium-independent catecholamine secretion evoked by 33 mM acetaldehyde. These findings suggest that the aminoindene antagonists interfere with the action of calcium and that in smooth muscle the antagonism is at an intracellular site involved in excitation-contraction coupling.