Location: Mosquito and Fly ResearchTitle: Cyclohexanol analogues are positive modulators of GABAA receptor currents and act as general anaesthetics in vivo) Author
Submitted to: European Journal of Pharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/22/2011
Publication Date: 6/1/2011
Publication URL: http://handle.nal.usda.gov/10113/55727
Citation: 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. 2011. Cyclohexanol analogues are positive modulators of GABAA receptor currents and act as general anaesthetics in vivo. European Journal of Pharmacology. 667:175-181. Interpretive Summary: Scientist at the USDA-ARS, Center for Medical, Agricultural, and Veterinary Entomology in Gainesville, FL, have collaborated with scientists at the University of Florida to synthesize new chemical compounds that function on GABAA receptors in the central nervous system of humans and other animals. Compounds that function on these receptors are used as general anesthetics when surgeries are performed. These novel compounds were derived from a chemical class known as cyclohexanols. Future design of novel cyclohexanol-based anesthetics may result as an outcome of this research. This research is useful to the medical community and to the general population through it’s benefit to patients.
Technical Abstract: GABAA 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 cyclohexanol were investigated on recombinant human '-aminobutyric acid (GABAA, a1ß2'2s) receptors expressed in xenopus oocytes, and compared to the modulatory effects on GABA currents observed with exposures to the intravenous anaesthetic agent, propofol. Submaximal EC20 GABA currents were typically enhanced by co-applications of 3–300 µM cyclohexanols. For instance, at 30 µM 2,6-diisopropylcyclohexanol (a novel compound) GABA responses were increased ~3-fold (although similar enhancements were achieved at 3 µM propofol). As regards rank order for modulation by the cyclohexanol analogues at 30 µM, the % enhancements for 2,6-dimethylcyclohexanol~2,6-diethylcyclohexanol~2,6-diisopropylcyclohexanol~2,6-di-secbutylcyclohexanol >>2,6-di-tert-butylcyclohexanol~4-tert-butylcyclohexanolNcyclohexanol>cyclopentanol~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 EC50s of 14.0 µM and 13.1µM respectively, while other cyclohexanols with bulkier side chains were less potent. In conclusion, our data indicate that cyclohexanols are both positive modulators of GABAA 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.