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Author (up) Hall, A.C.; Griffith, T.N.; Tsikolia, M.; Kotey, F.O.; Gill, N.; Humbert, D.J.; Watt, E.E.; Yermolina, Y.A.; Goel, S.; El-Ghendy, B.; Hall, C.D. file  url
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  Title Cyclohexanol analogues are positive modulators of GABA(A) receptor currents and act as general anaesthetics in vivo Type Journal Article
  Year 2011 Publication European Journal of Pharmacology Abbreviated Journal Eur J Pharmacol  
  Volume 667 Issue 1-3 Pages 175-181  
  Keywords Anesthetics, General/*pharmacology; Animals; Cyclohexanols/*chemistry/*pharmacology; *Electric Conductivity; Electrophysiological Processes/drug effects; Humans; Larva/drug effects/metabolism/physiology; Oocytes/metabolism; Receptors, GABA-A/genetics/*metabolism; Xenopus laevis/genetics  
  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 gamma-aminobutyric acid (GABA(A), alpha(1)beta(2)gamma(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 muM cyclohexanols. For instance, at 30 muM 2,6-diisopropylcyclohexanol (a novel compound) GABA responses were increased ~3-fold (although similar enhancements were achieved at 3 muM propofol). As regards rank order for modulation by the cyclohexanol analogues at 30 muM, 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~cyclopentan ol~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 muM and 13.1 muM 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.  
  Call Number Serial 509  
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Author (up) Hall, A.C.; Rowan, K.C.; Stevens, R.J.N.; Kelley, J.C.; Harrison, N.L. file  url
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  Title The effects of isoflurane on desensitized wild-type and alpha 1(S270H) gamma-aminobutyric acid type A receptors Type Journal Article
  Year 2004 Publication Anesthesia and Analgesia Abbreviated Journal Anesth Analg  
  Volume 98 Issue 5 Pages 1297-304, table of contents  
  Keywords Anesthetics, Inhalation/*pharmacology; Animals; DNA, Complementary/drug effects/genetics; Dose-Response Relationship, Drug; Humans; Isoflurane/*pharmacology; Kinetics; Mutation/genetics/physiology; Oocytes/metabolism; Receptors, GABA-A/*drug effects/*genetics; Xenopus  
  Abstract gamma-aminobutyric acid type A receptors (GABA(A)-R) mediate synaptic inhibition and meet many pharmacological criteria required of important general anesthetic targets. During synaptic transmission GABA release is sufficient to saturate, maximally activate, and transiently desensitize postsynaptic GABA(A)-Rs. The resulting inhibitory postsynaptic currents (IPSCs) are prolonged by volatile anesthetics like isoflurane. We investigated the effects of isoflurane on maximally activated and desensitized GABA(A)-R currents expressed in Xenopus oocytes. Wild-type alpha(1)beta(2) and alpha(1)beta(2)gamma(2s) receptors were exposed to 600 microM GABA until currents reached a steady-state desensitized level. At clinical concentrations (0.02-0.3 mM), isoflurane produced a dose-dependent enhancement of steady-state desensitized current in alpha(1)beta(2) receptors, an effect that was less apparent in receptors including a gamma(2s)-subunit. When serine at position 270 is mutated to histidine (alpha(1)(S270H)) in the second transmembrane segment of the alpha(1)-subunit, the currents evoked by sub-saturating concentrations of GABA became less sensitive to isoflurane enhancement. In addition, isoflurane enhancements of desensitized currents were greatly attenuated by this mutation and were undetectable in alpha(1)(S270H)beta(2)gamma(2s) receptors. In conclusion, isoflurane enhancement of GABA(A)-R currents evoked by saturating concentrations of agonist is subunit-dependent. The effects of isoflurane on desensitized receptors may be partly responsible for the prolongation of IPSCs during anesthesia. IMPLICATIONS: Isoflurane enhances desensitized gamma-aminobutyric acid type A receptor (GABA(A)-R) currents, an effect that is subunit-dependent and attenuated by a mutation in an alpha(1)-subunit pore residue of the GABA(A)-R. As GABA release at inhibitory synapses is typically saturating, isoflurane modulation of desensitized receptors may be partly responsible for prolongation of inhibitory postsynaptic currents during anesthesia.  
  Call Number Serial 506  
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