Calcium Antagonistic Properties of the Sesquiterpene T‐Cadinol and Related Substances: Structure‐Activity Studies

The calcium antagonistic properties of (+)-T-cadinol, some of its stereoisomers and related terpenes were investigated in both functional and radioligand binding studies, and the effects were compared with those of the dihydropyridine calcium antagonist (+/-)-nimodipine. In the isolated rat aorta, the terpenes relaxed contractions induced by 60 mM K+ more potently than those induced by phenylephrine. (+)-T-cadinol and its stereoisomers were the most potent among the terpenes to relax K(+)-induced contractions, whereas they were approximately 10,000 times less potent than (+/-)-nimodipine in this regard. Binding of the dihydropyridine radioligand [3H]-(+)-PN200-110 was studied on rat cerebral cortical membranes. Displacement and saturation studies indicated that (+)-T-cadinol caused a competitive inhibition of binding. The log Ki values for (+)-T-cadinol and (+/-)-nimodipine from displacement studies (-4.7 and -9.2) corresponded with the log RC50 values for relaxation of K(+)-contracted rat aortas (-5.0 and -9.0). For the terpenes, there was a significant correlation (P < 0.001, rs = 0.89) between displacement of dihydropyridine binding and the ability to relax K(+)-induced contractions. The structures of three terpenes were chemically modified by blocking hydroxyl groups. The potency of these derivatives, as well as the naturally occurring derivative-2-oxo-T-cadinol, to relax K(+)-induced contractions was not correlated to the lipophilicity of the compounds. Instead, other qualities appear to be of importance for the functional effects.(ABSTRACT TRUNCATED AT 250 WORDS)