Loreclezole is a sedative and anticonvulsant drug that acts as a positive allosteric modulator of GABAA receptors, selectively stimulating receptors containing β2 or β3 subunits[1]. Loreclezole is also an effective negative modulator of ρ1 GABAC receptors, with an IC50 of 0.5µM[2].
In vitro, Loreclezole (3-30µM) treatment of L929 fibroblasts increased the apparent desensitization degree and rate of whole-cell currents in a concentration-dependent manner at concentrations above 6µM. This effect is voltage-independent and is enhanced with increasing GABA concentrations[3].
In vivo, Loreclezole (5 mg/kg) administered intraperitoneally in amygdala-kindled epilepsy model rats significantly reduced seizure occurrences and afterdischarge duration[4]. In Lister Hooded rats, Loreclezole (0, 25, 50, or 75 mg/kg) dose-dependently increased the seizure threshold[5]. Loreclezole (50 mg/kg) administered orally in β2N265S transgenic mice did not show significant protective effects against pentylenetetrazol (PTZ)-induced seizures[6].
References:
[1] Wingrove P B, Wafford K A, Bain C, et al. The modulatory action of loreclezole at the gamma-aminobutyric acid type A receptor is determined by a single amino acid in the beta 2 and beta 3 subunit[J]. Proceedings of the National Academy of Sciences, 1994, 91(10): 4569-4573.
[2] Johnston G A R. Medicinal chemistry and molecular pharmacology of GABA-C receptors[J]. Current topics in medicinal chemistry, 2002, 2(8): 903-913.
[3] Donnelly J L, Macdonald R L. Loreclezole enhances apparent desensitization of recombinant GABAA receptor currents[J]. Neuropharmacology, 1996, 35(9-10): 1233-1241.
[4] Borowicz K K, Sawiniec A, Czuczwar S J. Interaction of loreclezole with conventional antiepileptic drugs in amygdala-kindled rats[J]. European neuropsychopharmacology, 2004, 14(3): 251-257.
[5] Green A R, Misra A, Murray T K, et al. A behavioural and neurochemical study in rats of the pharmacology of loreclezole, a novel allosteric modulator of the GABAA receptor[J]. Neuropharmacology, 1996, 35(9-10): 1243-1250.
[6]Groves J O, Guscott M R, Hallett D J, et al. The role of GABAAβ2 subunit‐containing receptors in mediating the anticonvulsant and sedative effects of loreclezole[J]. European Journal of Neuroscience, 2006, 24(1): 167-174.
Loreclezole是一种镇静剂和抗惊厥药，可作为 GABAA 受体正变构调节剂，选择性刺激含有β2或β3亚基的受体[1]。 Loreclezole对 ρ1 GABAC受体是一种有效的负调节剂，IC50为0.5µM[2]。
在体外，Loreclezole（3-30µM）处理L929 成纤维细胞，在浓度高于6 μM时，以浓度依赖性方式增强全细胞电流的表观脱敏程度和速率，这种效应与电压无关，并且随着GABA浓度的增加而增强[3]。
在体内，Loreclezole（5mg/kg）通过腹腔注射治疗杏仁核激发的癫痫模型大鼠，显著减少了癫痫发作和放电后持续时间[4]。Loreclezole（0、25、50或75 mg/kg）治疗Lister Hooded大鼠，剂量依赖性地升高了癫痫阈值[5]。Loreclezole（50 mg/kg）通过口服治疗β2N265S转基因小鼠，对戊四唑（PTZ）诱导的癫痫发作没有表现出明显的保护作用[6]。