Department of Molecular Structure and Characterization, Amgen Inc., Cambridge, Massachusetts, USA.
Department of Medicinal Chemistry, Amgen Inc., Cambridge, Massachusetts, USA.
Nat Struct Mol Biol. 2017 Feb;24(2):108-113. doi: 10.1038/nsmb.3329. Epub 2016 Dec 19.
Current therapies to treat persistent pain and neuropathic pain are limited by poor efficacy, side effects and risk of addiction. Here, we present a novel class of potent selective, central nervous system (CNS)-penetrant potentiators of glycine receptors (GlyRs), ligand-gated ion channels expressed in the CNS. AM-1488 increased the response to exogenous glycine in mouse spinal cord and significantly reversed mechanical allodynia induced by nerve injury in a mouse model of neuropathic pain. We obtained an X-ray crystal structure of human homopentameric GlyRα3 in complex with AM-3607, a potentiator of the same class with increased potency, and the agonist glycine, at 2.6-Å resolution. AM-3607 binds a novel allosteric site between subunits, which is adjacent to the orthosteric site where glycine binds. Our results provide new insights into the potentiation of cysteine-loop receptors by positive allosteric modulators and hold promise in structure-based design of GlyR modulators for the treatment of neuropathic pain.
目前用于治疗持续性疼痛和神经性疼痛的疗法疗效有限，且存在副作用和成瘾风险。在这里，我们提出了一类新型的甘氨酸受体（GlyRs）有效、选择性强、能穿透中枢神经系统（CNS）的激动剂。化合物 AM-1488 可增加小鼠脊髓中外源甘氨酸的反应，并显著逆转神经损伤诱导的神经性疼痛小鼠模型中的机械性痛觉过敏。我们获得了人同源五聚体 GlyRα3 与 AM-3607（一种具有更高效力的同类激动剂）和激动剂甘氨酸在 2.6-Å 分辨率下的复合物的 X 射线晶体结构。AM-3607 结合在亚基之间的一个新的变构位点，该位点与甘氨酸结合的正位点相邻。我们的结果为正变构调节剂对半胱氨酸环受体的增强作用提供了新的见解，并为基于结构的 GlyR 调节剂设计用于治疗神经性疼痛提供了希望。
