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)
Zygmunt
P M
PM
Department of Clinical Pharmacology, University Hospital of Lund, Sweden.
Larsson
B
B
Sterner
O
O
Vinge
E
E
Högestätt
E D
ED
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004095:Dihydropyridines / Q000378:metabolism; D005260:Female; D008024:Ligands; D009119:Muscle Contraction / Q000187:drug effects; D009124:Muscle Proteins / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009553:Nimodipine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D008024:Ligands; D009124:Muscle Proteins; D012717:Sesquiterpenes; D009553:Nimodipine; C072576:T-cadinol