CALCIUM ANTAGONISTIC PROPERTIES OF THE SESQUITERPENE T-CADINOL AND RELATED SUBSTANCES - STRUCTURE-ACTIVITY STUDIES

The calcium antagonistic properties of (+)-T-cadinol, some of its ster eoisomers and related terpenes were investigated in both functional an d radioligand binding studies, and the effects were compared with thos e of the dihydropyridine calcium antagonist (+/-)-nimodipine. In the i solated rat aorta, the terpenes relaxed contractions induced by 60 mM K+ more potently than those induced by phenylephrine. (+)-T-cadinol an d its stereoisomers were the most potent among the terpenes to relax K +-induced contractions, whereas they were approximately 10,000 times l ess potent than (+/-)-nimodipine in this regard. Binding of the dihydr opyridine radioligand [H-3]-(+)-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 K(i ) values for (+)-T-cadinol and (+/-)-nimodipine from displacement stud ies (-4.7 and -9.2) corresponded with the logRC50 values for relaxatio n of K+-contracted rat aortas (-5.0 and -9.0). For the terpenes, there was a significant correlation (P<0.001, r(s)=0.89) between displaceme nt of dihydropyridine binding and the ability to relax K+-induced cont ractions. The structures of three terpenes were chemically modified by blocking hydroxyl groups. The potency of these derivatives, as well a s the naturally occurring derivative 2-oxo-T-cadinol, to relax K+-indu ced contractions was not correlated to the lipophilicity of the compou nds. Instead, other qualities appear to be of importance for the funct ional effects. Our results suggest that (+)-T-cadinol and related terp enes may represent a new chemical class of calcium antagonists, which interact with dihydropyridine binding sites on the voltage-operated ca lcium channels.