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Anesthetics, GABA-Receptors, Patch-clamp techniques (Electrophysiology), Neuropharmacology, Electrophysiology, Chirality, Nuclear isomers, 2, 6-dimethlcyclohexanol isomers
General anesthetic compounds are used clinically to produce a loss of sensation during invasive procedures. Many anesthetic compounds consist of stereoisomers, although commonly used surgical anesthetics in clinical use, such as isoflurane, are not separated into individual stereoisomers. Nevertheless, studies have shown the importance of stereoselectivity of anesthetics in order to reach optimal drug effects. Neuronal GABAA receptors are known to be important target sites for many general anesthetic agents. A recent study showed positive modulation of GABAA receptor currents using 2,6-dimethylcyclohexanol and the novel compound 2,6-diisopropylcyclohexanol. The anesthetic potential of individual isomers of 2,6-dimethylcyclohexanol and 2,6-diisopropylcyclohexanol have not been fully studied to date. In this patch-clamp investigation, modulation of GABAA receptor currents with isomers of the potential novel anesthetic compounds, 2,6-dimethylcyclohexanol and 2,6 diisopropylcyclohexanol, were measured in human embryonic kidney cells stably expressing α1β3γ2s GABAA receptors. With increasing concentrations of 2,6-dimethycyclohexanol (1-300 μM) co-applied with 3 μM GABA, significant enhancement of GABAA receptor currents was observed at the higher doses (30- 300 μM) while inhibition of GABAA receptor currents was 5 observed at lower doses (1- 10 μM). Individual stereoisomers of 2,6-dimethycyclohexanol were then investigated. Although the application of trans,trans 2,6-dimethylcyclohexanol co-applied with 3 μM GABA resulted in an enhancement in the receptor currents compared to controls, cis,cis 2,6-dimethylcyclohexanol isomer resulted in the greatest enhancements in receptor currents. The cis,trans 2,6-dimethylcyclohexanol isomer did not modulate receptor activity. The application of 30 μM cis,cis 2,6-dimethycyclohexanol isomer in the presence of increasing GABA concentration (1-300 μM) resulted in a leftward shift of the GABA dose-response curve. Positive modulation of GABAA receptor currents by cis,cis 2,6-dimethylcyclohexanol demonstrated the highest potency compared with the mixture of isomers and the trans,trans and cis,trans isomers. Similarly, increasing 2,6-diisopropylcyclohexanol concentrations (1-300 μM) co-applied with 3 μM GABA resulted in an enhancement in the receptor currents compared with controls. In conclusion, we have demonstrated that cis,cis 2,6-dimethylcyclohexanol is a more potent positive modulator of GABAA receptor currents compared with mixtures of cyclohexanol isomers and a more potent anesthetic compared to trans,trans 2,6-dimethylcyclohexanol. Thus, cis,cis 2,6- dimethylcyclohexanol may be further developed as a novel high potency anesthetic for clinical use.
Chowdhury, Luvana, "Modulation of GABAA receptor currents by stereoisomers of the novel anesthetic compounds : ǂb2, 6-dimethylcyclohexanol and 2, 6-diisopropylcyclohexanol" (2013). Honors Project, Smith College, Northampton, MA.
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