title: 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.
authors.affiliation: Neuroscience Program, Departments of Biological Sciences (L.C., C.J.C., S.G., N.Z., A.C.-S.T., E.M.W., A.C.H.) and Chemistry (K.S., A.P., K.M.S.), Smith College, Northampton, Massachusetts; Department of Chemistry, University of Florida, Gainesville, Florida (C.D.H., D.J., G.G.P.); and Department of Chemistry, University of Tartu, Ravila, Estonia (G.G.P.).
authors.forename: Luvana
authors.initials: L
authors.lastname: Chowdhury
authors.affiliation: Neuroscience Program, Departments of Biological Sciences (L.C., C.J.C., S.G., N.Z., A.C.-S.T., E.M.W., A.C.H.) and Chemistry (K.S., A.P., K.M.S.), Smith College, Northampton, Massachusetts; Department of Chemistry, University of Florida, Gainesville, Florida (C.D.H., D.J., G.G.P.); and Department of Chemistry, University of Tartu, Ravila, Estonia (G.G.P.).
authors.forename: Celine J
authors.initials: CJ
authors.lastname: Croft
authors.affiliation: Neuroscience Program, Departments of Biological Sciences (L.C., C.J.C., S.G., N.Z., A.C.-S.T., E.M.W., A.C.H.) and Chemistry (K.S., A.P., K.M.S.), Smith College, Northampton, Massachusetts; Department of Chemistry, University of Florida, Gainesville, Florida (C.D.H., D.J., G.G.P.); and Department of Chemistry, University of Tartu, Ravila, Estonia (G.G.P.).
authors.forename: Shikha
authors.initials: S
authors.lastname: Goel
authors.affiliation: Neuroscience Program, Departments of Biological Sciences (L.C., C.J.C., S.G., N.Z., A.C.-S.T., E.M.W., A.C.H.) and Chemistry (K.S., A.P., K.M.S.), Smith College, Northampton, Massachusetts; Department of Chemistry, University of Florida, Gainesville, Florida (C.D.H., D.J., G.G.P.); and Department of Chemistry, University of Tartu, Ravila, Estonia (G.G.P.).
authors.forename: Naina
authors.initials: N
authors.lastname: Zaman
authors.affiliation: Neuroscience Program, Departments of Biological Sciences (L.C., C.J.C., S.G., N.Z., A.C.-S.T., E.M.W., A.C.H.) and Chemistry (K.S., A.P., K.M.S.), Smith College, Northampton, Massachusetts; Department of Chemistry, University of Florida, Gainesville, Florida (C.D.H., D.J., G.G.P.); and Department of Chemistry, University of Tartu, Ravila, Estonia (G.G.P.).
authors.forename: Angela C-S
authors.initials: AC
authors.lastname: Tai
authors.affiliation: Neuroscience Program, Departments of Biological Sciences (L.C., C.J.C., S.G., N.Z., A.C.-S.T., E.M.W., A.C.H.) and Chemistry (K.S., A.P., K.M.S.), Smith College, Northampton, Massachusetts; Department of Chemistry, University of Florida, Gainesville, Florida (C.D.H., D.J., G.G.P.); and Department of Chemistry, University of Tartu, Ravila, Estonia (G.G.P.).
authors.forename: Erin M
authors.initials: EM
authors.lastname: Walch
authors.affiliation: Neuroscience Program, Departments of Biological Sciences (L.C., C.J.C., S.G., N.Z., A.C.-S.T., E.M.W., A.C.H.) and Chemistry (K.S., A.P., K.M.S.), Smith College, Northampton, Massachusetts; Department of Chemistry, University of Florida, Gainesville, Florida (C.D.H., D.J., G.G.P.); and Department of Chemistry, University of Tartu, Ravila, Estonia (G.G.P.).
authors.forename: Kelly
authors.initials: K
authors.lastname: Smith
authors.affiliation: Neuroscience Program, Departments of Biological Sciences (L.C., C.J.C., S.G., N.Z., A.C.-S.T., E.M.W., A.C.H.) and Chemistry (K.S., A.P., K.M.S.), Smith College, Northampton, Massachusetts; Department of Chemistry, University of Florida, Gainesville, Florida (C.D.H., D.J., G.G.P.); and Department of Chemistry, University of Tartu, Ravila, Estonia (G.G.P.).
authors.forename: Alexandra
authors.initials: A
authors.lastname: Page
authors.affiliation: Neuroscience Program, Departments of Biological Sciences (L.C., C.J.C., S.G., N.Z., A.C.-S.T., E.M.W., A.C.H.) and Chemistry (K.S., A.P., K.M.S.), Smith College, Northampton, Massachusetts; Department of Chemistry, University of Florida, Gainesville, Florida (C.D.H., D.J., G.G.P.); and Department of Chemistry, University of Tartu, Ravila, Estonia (G.G.P.).
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Shea
authors.affiliation: Neuroscience Program, Departments of Biological Sciences (L.C., C.J.C., S.G., N.Z., A.C.-S.T., E.M.W., A.C.H.) and Chemistry (K.S., A.P., K.M.S.), Smith College, Northampton, Massachusetts; Department of Chemistry, University of Florida, Gainesville, Florida (C.D.H., D.J., G.G.P.); and Department of Chemistry, University of Tartu, Ravila, Estonia (G.G.P.).
authors.forename: C Dennis
authors.initials: CD
authors.lastname: Hall
authors.affiliation: Neuroscience Program, Departments of Biological Sciences (L.C., C.J.C., S.G., N.Z., A.C.-S.T., E.M.W., A.C.H.) and Chemistry (K.S., A.P., K.M.S.), Smith College, Northampton, Massachusetts; Department of Chemistry, University of Florida, Gainesville, Florida (C.D.H., D.J., G.G.P.); and Department of Chemistry, University of Tartu, Ravila, Estonia (G.G.P.).
authors.forename: D
authors.initials: D
authors.lastname: Jishkariani
authors.affiliation: Neuroscience Program, Departments of Biological Sciences (L.C., C.J.C., S.G., N.Z., A.C.-S.T., E.M.W., A.C.H.) and Chemistry (K.S., A.P., K.M.S.), Smith College, Northampton, Massachusetts; Department of Chemistry, University of Florida, Gainesville, Florida (C.D.H., D.J., G.G.P.); and Department of Chemistry, University of Tartu, Ravila, Estonia (G.G.P.).
authors.forename: Girinath G
authors.initials: GG
authors.lastname: Pillai
authors.affiliation: Neuroscience Program, Departments of Biological Sciences (L.C., C.J.C., S.G., N.Z., A.C.-S.T., E.M.W., A.C.H.) and Chemistry (K.S., A.P., K.M.S.), Smith College, Northampton, Massachusetts; Department of Chemistry, University of Florida, Gainesville, Florida (C.D.H., D.J., G.G.P.); and Department of Chemistry, University of Tartu, Ravila, Estonia (G.G.P.) ahall@science.smith.edu.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Hall
mesh_terms: D018681:Anesthetics, General / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D003511:Cyclohexanols / Q000737:chemistry* / Q000494:pharmacology*; D055724:Electrophysiological Phenomena / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D011487:Protein Conformation; D011963:Receptors, GABA-A / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C000619118:2,6-dimethylcyclohexanol; D018681:Anesthetics, General; D003511:Cyclohexanols; D011963:Receptors, GABA-A