Niclosamide is a Negative Allosteric Modulator of Group I Metabotropic Glutamate Receptors: Implications for Neuropathic Pain
Niclosamide is a Negative Allosteric Modulator of Group I Metabotropic Glutamate Receptors: Implications for Neuropathic Pain
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氯硝柳胺是 I 类代谢型谷氨酸受体的负变构调节剂：对神经性疼痛的影响
DOI：
10.1007/s11095-016-2027-9
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发表时间：
2016-12-01
影响因子：
3.7
通讯作者：
Welsh, William J.
中科院分区：
文献类型：
--
作者：
Ai, Ni;Wood, Richard D.;Welsh, William J.
目的神经病理性疼痛（NP）的治疗需要靶向特定的病理受体和通路。扩展我们以前的工作发表在本杂志上的第一组代谢型谷氨酸受体（mGluR）调节剂，我们现在调查的治疗潜力，氯硝柳胺在调节异常谷氨酸传输NP.MethodCalcium动员试验和交叉受体选择性实验进行表征氯硝柳胺的药理活性。一个集中的系列氯硝柳胺类似物，然后准备阐明药物-受体相互作用的计算分子建模分析出现的关键结构决定因素。最后，氯硝柳胺和氨基甲酸酯衍生物进行了研究，以评估其疗效在NP-诱发的机械性痛觉过敏模型rats. Results氯硝柳胺是一个低纳摩尔的变构拮抗剂组I mGluRs具有高选择性组I同源组III mGluRs。氯硝柳胺的酚羟基与mGluR 1/5形成关键的氢键。其生物活性共面构象通过B环上的硝基取代基和分子内键进一步稳定。机械性痛觉过敏在NP大鼠氯硝柳胺通过三种不同的剂量routine.ConclusionTo我们所知，这是第一次报告的水杨酰苯胺类化合物作为潜在的治疗NP。
PurposeNovel therapeutics are greatly needed that target specific pathological receptors and pathways involved in Neuropathic Pain (NP). Extending our previous work published in this Journal on Group I metabotropic glutamate receptor (mGluR) modulators, we now investigate the therapeutic potential of niclosamide in modulating aberrant glutamate transmission in NP.MethodCalcium mobilization assays and cross-receptor selectivity experiments are conducted to characterize the pharmacological activity of niclosamide. A focused series of niclosamide analogues is then prepared to elucidate key structural determinants that emerged from computational molecular modeling analysis on drug-receptor interactions. Finally, niclosamide and a carbamate derivative are studied to assess their efficacy in an NP-evoked mechanical hyperalgesia model in rats.ResultsNiclosamide is a low-nanomolar allosteric antagonist of Group I mGluRs with high selectivity for Group I over homologous Group III mGluRs. The phenolic hydroxyl group of niclosamide forms a crucial hydrogen bond with mGluR1/5. Its bioactive coplanar conformation is further stabilized by the nitro substituent on the B ring and an intramolecular bond. Mechanical hyperalgesia in NP rats is reversed by niclosamide through three different dosing routes.ConclusionTo our knowledge, this is the first report of the salicylanilide class of compounds as potential treatments for NP.