Donnelly J L, MacDonald R L
Department of Neurology, University of Michigan Medical Center, Ann Arbor 48104-1687, USA.
Neuropharmacology. 1996;35(9-10):1233-41. doi: 10.1016/s0028-3908(96)00053-6.
Loreclezole is a newly developed antiepileptic drug which has been shown to act at a specific site on beta 2 or beta 3 GABAA receptor subtypes to enhance the peak whole-cell response to submaximal concentrations of GABA. Potentiation by loreclezole occurred with high affinity only at GABAA receptors containing a beta 2 or beta 3 subtype, not a beta 1 subtype. We have studied the effect of loreclezole on whole-cell currents from recombinant GABAA receptors transiently expressed in L929 fibroblasts and on currents from cultured mouse cortical neurons and have found a second, inhibitory action of loreclezole that was independent of the beta-subunit subtype composition of the receptor. Loreclezole, at concentrations above 6 microM, enhanced the degree and rate of apparent desensitization of the whole-cell current in a concentration-dependent manner. This effect was voltage-independent, non-competitive and increased with increasing GABA concentration. The increase in desensitization was not blocked by the benzodiazepine antagonist flumazenil and did not require the presence of a gamma subunit. Loreclezole acted at a novel inhibitory allosteric site to increase the apparent desensitization of the GABAA receptor, regardless of its subunit composition. This activity of loreclezole may have implications for its experimental or clinical use as an antiepileptic drug.
洛雷唑是一种新开发的抗癫痫药物，已证明它作用于β2或β3 GABAA受体亚型的特定位点，以增强对亚最大浓度GABA的全细胞峰值反应。洛雷唑仅在含有β2或β3亚型而非β1亚型的GABAA受体上以高亲和力发生增强作用。我们研究了洛雷唑对在L929成纤维细胞中瞬时表达的重组GABAA受体的全细胞电流以及对培养的小鼠皮质神经元电流的影响，发现洛雷唑具有第二种抑制作用，该作用与受体的β亚基亚型组成无关。浓度高于6微摩尔时，洛雷唑以浓度依赖的方式增强全细胞电流的明显脱敏程度和速率。这种作用不依赖电压、非竞争性，且随GABA浓度增加而增强。脱敏作用的增强不受苯二氮䓬拮抗剂氟马西尼的阻断，也不需要γ亚基的存在。无论其亚基组成如何，洛雷唑作用于一个新的抑制性变构位点以增加GABAA受体的明显脱敏。洛雷唑的这种活性可能对其作为抗癫痫药物的实验或临床应用有影响。
