PT  - JOURNAL ARTICLE
AU  - Luvana Chowdhury
AU  - Celine J. Croft
AU  - Shikha Goel
AU  - Naina Zaman
AU  - Angela C.-S. Tai
AU  - Erin M. Walch
AU  - Kelly Smith
AU  - Alexandra Page
AU  - Kevin M. Shea
AU  - C. Dennis Hall
AU  - D. Jishkariani
AU  - Girinath G. Pillai
AU  - Adam C. Hall
TI  - Differential Potency of 2,6-Dimethylcyclohexanol Isomers for Positive Modulation of GABA<sub>A</sub> Receptor Currents
AID  - 10.1124/jpet.115.228890
DP  - 2016 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 570--579
VI  - 357
IP  - 3
4099  - http://jpet.aspetjournals.org/content/357/3/570.short
4100  - http://jpet.aspetjournals.org/content/357/3/570.full
SO  - J Pharmacol Exp Ther2016 Jun 01; 357
AB  - 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.