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

Zygmunt, P. M. LU orcid ; Larsson, B. LU ; Sterner, O. LU ; Vinge, E. LU and Högestätt, E. D. LU (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

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author
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publishing date
type
Contribution to journal
publication status
published
subject
in
Pharmacology and Toxicology
volume
73
issue
1
pages
7 pages
publisher
Wiley-Blackwell
external identifiers
  • pmid:8234189
  • scopus:0027275087
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&lt;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}},
}