Differential Potency of 2,6-Dimethylcyclohexanol Isomers for Positive Modulation of GABAA Receptor Currents

Abstract

GABAA receptors meet all of the pharmacological requirements necessary to be considered important targets for the action of general anesthetic agents in the mammalian brain. In the following patch-clamp study, the relative modulatory effects of 2,6-dimethylcyclohexanol diastereomers were investigated on human GABAA (α1β3γ2s) receptor currents stably expressed in human embryonic kidney cells. Cis,cis-, trans,trans-, and cis,trans-isomers were isolated from commercially available 2,6-dimethylcyclohexanol and were tested for positive modulation of submaximal GABA responses. For example, the addition of 30 μM cis,cis-isomer resulted in an approximately 2- to 3-fold enhancement of the EC20 GABA current. Coapplications of 30 μM 2,6-dimethylcyclohexanol isomers produced a range of positive enhancements of control GABA responses with a rank order for positive modulation: cis,cis > trans,trans ≥ mixture of isomers > > cis,trans-isomer. In molecular modeling studies, the three cyclohexanol isomers bound with the highest binding energies to a pocket within transmembrane helices M1 and M2 of the β3 subunit through hydrogen-bonding interactions with a glutamine at the 224 position and a tyrosine at the 220 position. The energies for binding to and hydrogen-bond lengths within this pocket corresponded with the relative potencies of the agents for positive modulation of GABAA receptor currents (cis,cis > trans,trans > cis,trans-2,6-dimethylcyclohexanol). In conclusion, the stereochemical configuration within the dimethylcyclohexanols is an important molecular feature in conferring positive modulation of GABAA receptor activity and for binding to the receptor, a consideration that needs to be taken into account when designing novel anesthetics with enhanced therapeutic indices.

Antagonistic postsynaptic and presynaptic actions of cyclohexanol on neuromuscular synaptic transmission and function

“…Cyclohexanol also modulates GABA A receptor function in the CNS (Hall et al 2011;Chowdhury et al 2016) but to our knowledge the present study comprises the first electrophysiological investigation of the actions of a cyclic alcohol on NMJs. Whole-cell currents mediated by neuronal nAChRs, expressed in snail neurones are inhibited by cyclohexanol and by several other cyclic alcohols (McKenzie et al 1995).…”

A GABA Receptor Modulator and Semiochemical Compounds Evidenced Using Volatolomics as Candidate Markers of Chronic Exposure to Fipronil in Apis mellifera

“…Fipronil is a systemic insecticide acting on the gamma-aminobutyric acid receptor (GABA-R) leading to the closure of chloride channels and a persistent nerve signal. Among the identified VOCs, 2,6-dimethylcyclohexanol is described in the literature as a GABA-R modulator [ 34 ]. This compound binds to GABA-R on a different binding site than GABA and via an allosteric effect causes a prolonged opening of chloride channels.…”

Increasing the steric hindrance around the catalytic core of a self-assembled imine-based non-heme iron catalyst for C–H oxidation

“…5-Triisopropylsilyl-pyridine-2-carboxaldehyde 11,13 and 5-triisopropylsilyl-2-picolylamine 11 b were prepared according to literature procedure and spectral data were in accordance with those reported. Menthyl acetate 14 and 2,6-dimethylcyclohexanol 15 were prepared according to literature procedures and spectral data were in accordance with those reported.…”