Molecular Biomedicine, School of Medical Sciences, University of Sydney, Sydney, Australia (C.I.G., D.A.H., R.J.V.) and Biomedical Science, School of Health and Behavioural Sciences and Sunshine Coast Health Institute, University of the Sunshine Coast, Maroochydore, Australia (R.J.H.).
Molecular Biomedicine, School of Medical Sciences, University of Sydney, Sydney, Australia (C.I.G., D.A.H., R.J.V.) and Biomedical Science, School of Health and Behavioural Sciences and Sunshine Coast Health Institute, University of the Sunshine Coast, Maroochydore, Australia (R.J.H.)
Pharmacol Rev. 2022 Oct;74(4):933-961. doi: 10.1124/pharmrev.122.000583.
Glycine receptors are ligand-gated ion channels that mediate synaptic inhibition throughout the mammalian spinal cord, brainstem, and higher brain regions. They have recently emerged as promising targets for novel pain therapies due to their ability to produce antinociception by inhibiting nociceptive signals within the dorsal horn of the spinal cord. This has greatly enhanced the interest in developing positive allosteric modulators of glycine receptors. Several pharmaceutical companies and research facilities have attempted to identify new therapeutic leads by conducting large-scale screens of compound libraries, screening new derivatives from natural sources, or synthesizing novel compounds that mimic endogenous compounds with antinociceptive activity. Advances in structural techniques have also led to the publication of multiple high-resolution structures of the receptor, highlighting novel allosteric binding sites and providing additional information for previously identified binding sites. This has greatly enhanced our understanding of the functional properties of glycine receptors and expanded the structure activity relationships of novel pharmacophores. Despite this, glycine receptors are yet to be used as drug targets due to the difficulties in obtaining potent, selective modulators with favorable pharmacokinetic profiles that are devoid of side effects. This review presents a summary of the structural basis for how current compounds cause positive allosteric modulation of glycine receptors and discusses their therapeutic potential as analgesics. SIGNIFICANCE STATEMENT: Chronic pain is a major cause of disability, and in Western societies, this will only increase as the population ages. Despite the high level of prevalence and enormous socioeconomic burden incurred, treatment of chronic pain remains limited as it is often refractory to current analgesics, such as opioids. The National Institute for Drug Abuse has set finding effective, safe, nonaddictive strategies to manage chronic pain as their top priority. Positive allosteric modulators of glycine receptors may provide a therapeutic option.
甘氨酸受体是配体门控离子通道，可介导整个哺乳动物脊髓、脑干和大脑区域的突触抑制。由于它们能够通过抑制脊髓背角中的伤害性信号来产生抗伤害作用，因此它们最近成为新型疼痛疗法的有希望的靶标。这极大地提高了开发甘氨酸受体正变构调节剂的兴趣。几家制药公司和研究机构试图通过对化合物库进行大规模筛选、筛选天然来源的新衍生物或合成具有抗伤害活性的内源性化合物模拟物来识别新的治疗先导物。结构技术的进步也导致了受体的多个高分辨率结构的发表，突出了新的变构结合位点，并为先前鉴定的结合位点提供了更多信息。这极大地提高了我们对甘氨酸受体功能特性的理解，并扩展了新型药效团的结构活性关系。尽管如此，由于难以获得具有有利药代动力学特性且无副作用的有效、选择性调节剂，甘氨酸受体尚未被用作药物靶点。本综述总结了当前化合物引起甘氨酸受体正变构调节的结构基础，并讨论了它们作为镇痛药的治疗潜力。意义陈述：慢性疼痛是残疾的主要原因，在西方社会，随着人口老龄化，这种情况只会增加。尽管患病率很高，给社会经济造成的负担巨大，但慢性疼痛的治疗仍然有限，因为它通常对目前的镇痛药（如阿片类药物）有抗药性。国家药物滥用研究所将寻找有效、安全、无成瘾性的策略来管理慢性疼痛作为他们的首要任务。甘氨酸受体的正变构调节剂可能提供一种治疗选择。
