(+)- And (−)-borneol: efficacious positive modulators of GABA action at human recombinant α1β2γ2L GABAA receptors

Abstract (+)-Borneol is a bicyclic monoterpene used for analgesia and anaesthesia in traditional Chinese and Japanese medicine and is found in the essential oils of medicinal herbs, such as valerian. (+)-Borneol was found to have a highly efficacious positive modulating action at GABA A receptors, as did its enantiomer (−)-borneol. The effects of these bicyclic monoterpenes alone and with GABA were evaluated at recombinant human α 1 β 2 γ 2L GABA A receptors expressed in Xenopus laevis oocytes using two-electrode voltage-clamp electrophysiology. (+)-Borneol (EC 50 248 μM) and (−)-borneol (EC 50 237 μM) enhanced the action of low concentrations of GABA by more than 1000%. These enhancing effects were highly dependent on the relative concentrations of the borneol enantiomer and GABA, and were insensitive to flumazenil indicating that (+)- and (−)-borneol were not acting at classical benzodiazepine sites. The maximal responses to GABA were enhanced 19% by (+)-borneol and reduced 21% by (−)-borneol. The borneol analogues isoborneol, (−)-bornyl acetate and camphor, produced less marked effects. At high concentrations (>1.5 mM) (+)- and (−)-borneol directly activated GABA A receptors producing 89% and 84%, respectively, of the maximal GABA response indicative of a weak partial agonist action. Although of lower potency, the highly efficacious positive modulatory actions of (+)- and (−)-borneol on GABA responses were at least equivalent to that of the anaesthetic etomidate and much greater than that of diazepam or 5α-pregnan-3α-ol-20-one. The relatively rigid cage structure of these bicyclic monoterpenes and their high efficacy may aid in a greater understanding of molecular aspects of positive modulation of the activation of GABA A receptors.