Author: Hall, A.C.; Griffith, T.N.; Tsikolia, M.; Kotey, F.O.; Gill, N.; Humbert, D.J.; Watt, E.E.; Yermolina, Y.A.; Goel, S.; El-Ghendy, B.; Hall, C.D.
Description: GABA(A) receptors meet all the pharmacological criteria required to be considered important general anaesthetic targets. In the following study, the modulatory effects of various commercially available and novel cyclohexanols were investigated on recombinant human gamma-aminobutyric acid (GABA(A), alpha(1)beta(2)gamma(2s)) receptors expressed in Xenopus oocytes, and compared to the modulatory effects on GABA currents observed with exposures to the intravenous anaesthetic agent, propofol. Submaximal EC(20) GABA currents were typically enhanced by co-applications of 3-300 muM cyclohexanols. For instance, at 30 muM 2,6-diisopropylcyclohexanol (a novel compound) GABA responses were increased ~3-fold (although similar enhancements were achieved at 3 muM propofol). As regards rank order for modulation by the cyclohexanol analogues at 30 muM, the % enhancements for 2,6-dimethylcyclohexanol~2,6-diethylcyclohexanol~2,6-diisopropylcyclohexanol~2,6- di-sec-butylcyclohexanol >>2,6-di-tert-butylcyclohexanol~4-tert-butylcyclohexanol>cyclohexanol~cyclopentan ol~2-methylcyclohexanol. We further tested the potencies of the cyclohexanol analogues as general anaesthetics using a tadpole in vivo assay. Both 2,6-diisopropylcyclohexanol and 2,6-dimethylcyclohexanol were effective as anaesthetics with EC(50)s of 14.0 muM and 13.1 muM respectively, while other cyclohexanols with bulkier side chains were less potent. In conclusion, our data indicate that cyclohexanols are both positive modulators of GABA(A) receptors currents and anaesthetics. The positioning and size of the alkyl groups at the 2 and 6 positions on the cyclohexanol ring were critical determinants of activity.
Subject headings: Anesthetics, General/pharmacology; Animals; Cyclohexanols/chemistry/pharmacology; Electric Conductivity; Electrophysiological Processes/drug effects; Humans; Larva/drug effects/metabolism/physiology; Oocytes/metabolism; Receptors, GABA-A/genetics/metabolism; Xenopus laevis/genetics
Publication year: 2011
Journal or book title: European Journal of Pharmacology
Volume: 667
Issue: 1-3
Pages: 175-181
Find the full text : http://www.sciencedirect.com/science/article/pii/S0014299911006418
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Type: Journal Article
Serial number: 509