The clobazam metabolite N-desmethyl clobazam is an α2 preferring benzodiazepine with an improved therapeutic window for antihyperalgesia.
The clobazam metabolite N-desmethyl clobazam is an α2 preferring benzodiazepine with an improved therapeutic window for antihyperalgesia.
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DOI：
10.1016/j.neuropharm.2016.07.004
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发表时间：
2016-10
影响因子：
4.7
通讯作者：
Besson M
中科院分区：
文献类型：
--
作者：
Ralvenius WT;Acuña MA;Benke D;Matthey A;Daali Y;Rudolph U;Desmeules J;Zeilhofer HU;Besson M
来自转基因小鼠的数据表明，苯二氮(BDZ)位点激动剂对α2亚型GABA受体(α2GABAAR)具有更高的选择性，可能有助于治疗神经病理性疼痛。可用于啮齿动物临床前试验的亚型选择性化合物支持这一概念，但尚未被批准用于人类，阻碍了患者的概念验证研究。我们最近提出，BDZ氯巴扎姆(CBZ)的主要代谢物N-去甲基氯巴扎姆(NDMC)是CBZ给药后小鼠所观察到的大部分抗痛敏作用的机制。为了评估NDMC的潜在药理学特性，我们分析了CBZ、NDMC和安定(DZP)在重组受体中GABAAR亚型特异性的差异。DZP和CBZ增强镇静α1GABAARs和抗痛敏α2GABAARs的作用相似，而NDMC在较宽的浓度范围内偏好α2GABAARs而不是α1GABAARs。在体内，DZP和NDMC在3到30 mg/kg的剂量下可以减少神经病理性疼痛。在这些剂量下，DZP具有较强的运动镇静作用，而NDMC没有或仅有较弱的镇静作用。当NDMC的作用仅限于α-1GABAARs时，其镇静作用明显。然而，当对GABAAR点突变小鼠进行分离分析抗痛敏和镇静作用时，我们发现，与DZP相比，NDMC有一个显著改善的治疗窗口，这与其更有利的α2/α1体外活性比率一致。鉴于NDMC应该与其母化合物CBZ具有相同的安全性，它应该非常适合在人类志愿者或患者身上进行概念验证研究。N-去甲基氯巴赞是批准的氯巴扎姆的天然代谢物。N-去甲基氯巴坦具有较高的α-2/α-1 GABA选择性比。在非镇静剂量下，它对神经性疼痛有显著的止痛作用。N-去甲基氯巴扎姆可能非常适合于人类的概念验证研究。
Data from genetically modified mice suggest that benzodiazepine (BDZ)-site agonists with improved selectivity for α2-subtype GABAA receptors (α2GABAAR) are potentially useful for the treatment of neuropathic pain. Subtype-selective compounds available for preclinical tests in rodents support this concept but have not been approved for human use, hindering proof-of-concept studies in patients. We recently proposed that N-desmethyl clobazam (NDMC), the main metabolite of the licensed BDZ clobazam (CBZ), is responsible for most of the antihyperalgesia observed in mice after CBZ administration. In order to assess a potentially favorable pharmacological profile of NDMC, we analyzed differences in the GABAAR subtype specificity of CBZ, NDMC and diazepam (DZP) in recombinant receptors. DZP and CBZ potentiated sedating α1GABAARs and antihyperalgesic α2GABAARs with similar efficacies, whereas NDMC preferred α2GABAARs over α1GABAARs across a wide concentration range. In vivo, DZP and NDMC reduced neuropathic pain at doses between 3 and 30 mg/kg. At these doses, DZP had strong locomotor sedating effects while NDMC caused no or only weak sedation. Sedative effects of NDMC became apparent when the action of NDMC was restricted to α1GABAARs. However, when GABAAR point-mutated mice were studied that allow the analysis of antihyperalgesia and sedation in isolation, we found that, compared to DZP, NDMC had a significantly improved therapeutic window, consistent with its more favorable α2/α1 in vitro activity ratio. Given that NDMC should share the safety profile of its parent compound CBZ, it should be well-suited for proof-of-concept studies in human volunteers or patients. N-desmethyl clobazam is a naturally occurring metabolite of the approved clobazam. N-desmethyl clobazam possesses an improved α2/α1 GABAAR selectivity ratio. It exerts significant analgesia against neuropathic pain at non-sedative doses. N-desmethyl clobazam may be a well-suited for proof-of-concept studies in humans.