Positive Allosteric Modulators of Glycine Receptors and Their Potential Use in Pain Therapies.

IF 19.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY
Casey I Gallagher, Damien A Ha, Robert J Harvey, Robert J Vandenberg
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引用次数: 2

Abstract

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.

甘氨酸受体的正变构调节剂及其在疼痛治疗中的潜在应用。
甘氨酸受体是配体门控的离子通道,介导哺乳动物脊髓、脑干和大脑高级区域的突触抑制。由于它们能够通过抑制脊髓背角内的伤害感受信号产生抗伤害感受,因此最近成为新型疼痛疗法的有希望的靶点。这大大增强了人们对开发甘氨酸受体的正变构调节剂的兴趣。一些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,从天然来源筛选新的衍生物,或合成模拟具有抗伤害感受活性的内源性化合物的新化合物,来确定新的治疗线索。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,并为先前确定的结合位点提供了额外的信息。这大大增强了我们对甘氨酸受体功能特性的理解,并扩展了新药效团的结构-活性关系。尽管如此,由于难以获得具有良好药代动力学特征且无副作用的强效选择性调节剂,甘氨酸受体尚未被用作药物靶点。本文综述了目前化合物如何引起甘氨酸受体的正变构调节的结构基础,并讨论了它们作为镇痛剂的治疗潜力。意义陈述:慢性疼痛是导致残疾的主要原因,在西方社会,这种情况只会随着人口老龄化而增加。尽管慢性疼痛的发病率很高,造成了巨大的社会经济负担,但其治疗仍然有限,因为目前的止痛药(如阿片类药物)往往难以治疗。美国国家药物滥用研究所将寻找有效、安全、非成瘾的策略来管理慢性疼痛作为首要任务。甘氨酸受体的阳性变构调节剂可以提供治疗选择。
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来源期刊
Pharmacological Reviews
Pharmacological Reviews 医学-药学
CiteScore
34.70
自引率
0.50%
发文量
40
期刊介绍: Pharmacological Reviews is a highly popular and well-received journal that has a long and rich history of success. It was first published in 1949 and is currently published bimonthly online by the American Society for Pharmacology and Experimental Therapeutics. The journal is indexed or abstracted by various databases, including Biological Abstracts, BIOSIS Previews Database, Biosciences Information Service, Current Contents/Life Sciences, EMBASE/Excerpta Medica, Index Medicus, Index to Scientific Reviews, Medical Documentation Service, Reference Update, Research Alerts, Science Citation Index, and SciSearch. Pharmacological Reviews offers comprehensive reviews of new pharmacological fields and is able to stay up-to-date with published content. Overall, it is highly regarded by scholars.
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