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

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Abstract

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. Our results suggest that (+)‐T‐cadinol and related terpenes may represent a new chemical class of calcium antagonists, which interact with dihydropyridine binding sites on the voltage‐operated calcium channels. 1993 Nordic Pharmacological Society

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Authors
External organisations
  • Skåne University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Pharmacology and Toxicology
Original languageEnglish
Pages (from-to)3-9
Number of pages7
JournalPharmacology & Toxicology
Volume73
Issue number1
Publication statusPublished - 1993 Jan 1
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes