Calcium Antagonistic Properties of the Sesquiterpene T‐Cadinol and Related Substances : Structure‐Activity Studies
(1993) In Pharmacology and Toxicology 73(1). p.3-9- 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... (More)
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
(Less)
- author
- Zygmunt, P. M. LU ; Larsson, B. LU ; Sterner, O. LU ; Vinge, E. LU and Högestätt, E. D. LU
- publishing date
- 1993-01-01
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Pharmacology and Toxicology
- volume
- 73
- issue
- 1
- pages
- 7 pages
- publisher
- Wiley-Blackwell
- external identifiers
-
- scopus:0027275087
- pmid:8234189
- ISSN
- 0901-9928
- DOI
- 10.1111/j.1600-0773.1993.tb01948.x
- language
- English
- LU publication?
- no
- id
- c6c36e30-b036-4614-8977-f0d0e6b98602
- date added to LUP
- 2019-05-31 21:42:53
- date last changed
- 2024-02-15 10:59:31
@article{c6c36e30-b036-4614-8977-f0d0e6b98602, abstract = {{<p>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<sup>+</sup> more potently than those induced by phenylephrine. (+)‐T‐cadinol and its stereoisomers were the most potent among the terpenes to relax K<sup>+</sup>‐induced contractions, whereas they were approximately 10,000 times less potent than (±)‐nimodipine in this regard. Binding of the dihydropyridine radioligand [<sup>3</sup>H]‐(+)‐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<sub>i</sub> values for (+)‐T‐cadinol and (±)‐nimodipine from displacement studies (−4.7 and −9.2) corresponded with the log RC<sub>50</sub> values for relaxation of K<sup>+</sup>‐contracted rat aortas (−5.0 and −9.0). For the terpenes, there was a significant correlation (P<0.001, r<sub>s</sub> = 0.89) between displacement of dihydropyridine binding and the ability to relax K<sup>+</sup>‐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<sup>+</sup>‐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</p>}}, author = {{Zygmunt, P. M. and Larsson, B. and Sterner, O. and Vinge, E. and Högestätt, E. D.}}, issn = {{0901-9928}}, language = {{eng}}, month = {{01}}, number = {{1}}, pages = {{3--9}}, publisher = {{Wiley-Blackwell}}, series = {{Pharmacology and Toxicology}}, title = {{Calcium Antagonistic Properties of the Sesquiterpene T‐Cadinol and Related Substances : Structure‐Activity Studies}}, url = {{http://dx.doi.org/10.1111/j.1600-0773.1993.tb01948.x}}, doi = {{10.1111/j.1600-0773.1993.tb01948.x}}, volume = {{73}}, year = {{1993}}, }