title: Cyclohexanol analogues are positive modulators of GABA(A) receptor currents and act as general anaesthetics in vivo.
abstract: 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 γ-aminobutyric acid (GABA(A), α(1)β(2)γ(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 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-sec-butylcyclohexanol ≫2,6-di-tert-butylcyclohexanol~4-tert-butylcyclohexanol>cyclohexanol~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 EC(50)s of 14.0 μM and 13.1 μM 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.
authors.affiliation: Neuroscience Program, Department of Biological Sciences, Smith College, Northampton, MA 01063, USA. ahall@science.smith.edu
authors.forename: Adam C
authors.initials: AC
authors.lastname: Hall
authors.forename: Theanne N
authors.initials: TN
authors.lastname: Griffith
authors.forename: Maia
authors.initials: M
authors.lastname: Tsikolia
authors.forename: Francesca O
authors.initials: FO
authors.lastname: Kotey
authors.forename: Nikhila
authors.initials: N
authors.lastname: Gill
authors.forename: Danielle J
authors.initials: DJ
authors.lastname: Humbert
authors.forename: Erin E
authors.initials: EE
authors.lastname: Watt
authors.forename: Yuliya A
authors.initials: YA
authors.lastname: Yermolina
authors.forename: Shikha
authors.initials: S
authors.lastname: Goel
authors.forename: Bahaa
authors.initials: B
authors.lastname: El-Ghendy
authors.forename: C Dennis
authors.initials: CD
authors.lastname: Hall
mesh_terms: D018681:Anesthetics, General / Q000494:pharmacology*; D000818:Animals; D003511:Cyclohexanols / Q000737:chemistry* / Q000494:pharmacology*; D004553:Electric Conductivity; D055724:Electrophysiological Phenomena / Q000187:drug effects; D006801:Humans; D007814:Larva / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009865:Oocytes / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000235:genetics
chemical_list: D018681:Anesthetics, General; D003511:Cyclohexanols; D011963:Receptors, GABA-A