Granger Renee E, Campbell Erica L, Johnston Graham A R
Adrien Albert Laboratory of Medicinal Chemistry, Department of Pharmacology, Faculty of Medicine, The University of Sydney, Sydney, NSW 2006, Australia.
Biochem Pharmacol. 2005 Apr 1;69(7):1101-11. doi: 10.1016/j.bcp.2005.01.002.
(+)-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 alpha(1)beta(2)gamma(2L) GABA(A) receptors expressed in Xenopus laevis oocytes using two-electrode voltage-clamp electrophysiology. (+)-Borneol (EC(50) 248microM) and (-)-borneol (EC(50) 237microM) 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 (>1.5mM) (+)- 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 5alpha-pregnan-3alpha-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.
（+）-冰片是一种双环单萜，在中国传统医学和日本医学中用于镇痛和麻醉，存在于药用植物如缬草的精油中。已发现（+）-冰片在GABA（A）受体上具有高效的正向调节作用，其对映体（-）-冰片也是如此。使用双电极电压钳电生理学，在非洲爪蟾卵母细胞中表达的重组人α（1）β（2）γ（2L）GABA（A）受体上评估了这些双环单萜单独以及与GABA一起的作用。（+）-冰片（EC50为248μM）和（-）-冰片（EC50为237μM）使低浓度GABA的作用增强了1000％以上。这些增强作用高度依赖于冰片对映体和GABA的相对浓度，并且对氟马西尼不敏感，表明（+）-和（-）-冰片并非作用于经典的苯二氮䓬位点。（+）-冰片使对GABA的最大反应增强了19％，而（-）-冰片使其降低了21％。冰片类似物异冰片、（-）-乙酸冰片酯和樟脑产生的作用不太明显。在高浓度（>1.5mM）时，（+）-和（-）-冰片直接激活GABA（A）受体，分别产生最大GABA反应的89％和84％，表明具有弱部分激动剂作用。尽管效力较低，但（+）-和（-）-冰片对GABA反应的高效正向调节作用至少与麻醉药依托咪酯相当，且远大于地西泮或5α-孕烷-3α-醇-20-酮。这些双环单萜相对刚性的笼状结构及其高效性可能有助于更深入地理解GABA（A）受体激活的正向调节的分子方面。
