Synthesis and pharmacological evaluation of reduced diastereoisomeric and quaternary ammonium derivatives of calcium antagonistic (methylenedioxy)indenes on the isolated rat aorta.

Based upon findings that 2-n-propyl- and 2-n-butyl-3-(diethylamino)-5,6-(methylenedioxy)indenes (1 and 2) inhibit a variety of calcium-activated cellular processes, it has previously been proposed that these compounds act as calcium antagonists with an intracellular site of action. In the present investigation, the diastereoisomeric dihydro analogues, cis- and trans-2-n-propyl- and cis- and trans-2-n-butyl-1-(dimethylamino)-5,6-(methylenedioxy)indans (5--8), and the trimethyl quaternary ammonium analogues of the unsaturated (3 and 4) and cis-saturated (9 and 10) systems were synthesized, and the ability of each to reverse norepinephrine- or KCl-induced contraction of the rat aorta was assessed. Saturation of 1 or 2 to produce the corresponding cis-aminoindan analogues (5 and 7) yielded compounds of similar spasmolytic activity, while saturation which yielded the respective trans forms (6 and 8) resulted in significant loss of potency. Methylation of either the cis unsaturated or saturated compounds to yield their respective quaternary derivatives also significantly reduced the potency of each compound. The reduced activity of the quaternary derivatives might be anticipated because of the limited cellular penetration of such compounds and is taken as evidence that the active tertiary analogues have an intracellular site of action. However, the results of the present investigation do not preclude the contribution of membrane effects to the pharmacological activity of the tertiary compounds (1, 2, 5, and 7), since the spasmolytically active analogues demonstrated a somewhat greater antagonistic potency against KCl-induced contractions as compared to their antagonism of the effects of norepinephrine.