New Glycinergic Modulators as Potent Painkillers without Negative Psychoactive Effects - Supplement

新型甘氨酸调节剂作为有效的止痛药，没有负面的精神影响 - 补充

• 批准号: 10054996
• 负责人: PEI TANG
• 金额: $ 14.09万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054996
• 关键词: Absence of pain sensation; Address; Affinity; Analgesics; Binding; Binding Proteins; Biological Assay; Biological Availability; Blood; Brain; Clinic; Clinical; Contractor; Cytochrome P450; Development; Drug Binding Site; Electrophysiology (science); Flow Cytometry; Glycine Receptors; Human; In Vitro; Investigational Drugs; Ion Channel; Kidney; Knockout Mice; Lead; Liver; Lung; Marijuana; Measurement; Measures; Mediating; Molecular; Morphine; Mus; National Institute of Mental Health; New Drug Approvals; Opioid Analgesics; Opioid Receptor; Pain Measurement; Pain management; Pharmaceutical Preparations; Phase; Plasma; Plasma Proteins; Population; Psychotropic Drugs; Resolution; Rodent; Site; Specificity; Spleen; Structure; Time; Transmembrane Domain; addiction; analog; base; cannabinoid receptor; chronic pain; design; drug discovery; improved; in silico; in vivo; inflammatory neuropathic pain; inflammatory pain; innovation; lead optimization; next generation; non-opioid analgesic; novel; novel therapeutics; opioid epidemic; opioid overuse; pain model; painful neuropathy; public health relevance; scaffold; screening; screening program; virtual screening

One third of the US population suffers from chronic pain, but the existing treatment options are inadequate. The overuse of opioid painkillers has contributed to the current opioid epidemic crisis. In this Blueprint Neurotherapeutics Network application, we propose to bring a novel class of potent non-opioid painkillers to the clinic. Using high-resolution structures of human glycine receptors (hGlyRs), we discovered a unique drug-binding site in the transmembrane domain that is responsible for mediating the non-psychoactive analgesic effects of marijuana. Using an innovative ensemble-based virtual screening approach to target this unique site, followed by in vitro electrophysiology measurements of functional modulation and in vivo measurements of pain treatment in an inflammatory pain model in mice, we discovered a new molecular scaffold that is GlyR subtype specific. The top hits of this scaffold are 10-100 times more potent than morphine in suppressing inflammatory pain. Moreover, the top hits can reduce the morphine requirement by a factor of 50 to achieve the same level of analgesia. In the preparatory (UG3) phase of this project, we will establish a lead development team with BPN consultants and solidify the scaffold's clinical value by evaluating the efficacy of the top hits in treating neuropathic pain. We will then move to the drug discovery (UH3) phase to complete the hit-to-lead optimization via the following three specific aims: (1) Maximize the potency and efficacy of new hits through (a) in silico SAR exploration to improve ADMET profiles and optimize binding affinity, (b) synthesizing the designed analogs by BPN contractors, and (c) evaluating the synthesized analogs in vitro using electrophysiology as the primary assay and in vivo using rodent inflammatory and neuropathic pain models as secondary assays. (2) Perform ADMET assays for the top analogs, focusing on bioavailability profiling, brain-to-plasma distribution, microsomal stability, plasma protein binding, cytochrome P450 (CYP) induction and inhibition, Ames activity, and flow cytometry of toxic markers in the liver, spleen, blood, lung, kidney, and brain. (3) Establish specificity through in vivo pain model measurements in α3- GlyR knockout mice using analogs with favorable ADMET profiles to confirm the intended target. Counter-screening of off-target effects on opioid receptors, cannabinoid receptors, and other ion channels will be measured by the psychoactive drug screening program (PDSP) at NIMH. We aim to identify a single lead compound for the FDA investigational new drug approval by the end of the UH3 phase.

三分之一的美国人口患有慢性疼痛，但现有的治疗方案 阿片类止痛药的过度使用导致了当前阿片类药物的流行。 在这个蓝图神经治疗网络应用程序中，我们建议带来一种新颖的危机。 使用高分辨率人体结构将一类强效非阿片类止痛药推向临床。 甘氨酸受体（hGlyRs），我们在跨膜中发现了一个独特的药物结合位点 负责介导大麻的非精神活性镇痛作用的域。 使用创新的基于整体的虚拟筛选方法来瞄准这个独特的地点， 随后进行功能调节的体外电生理学测量和体内 在对小鼠炎症性疼痛模型中的疼痛治疗进行测量时，我们发现了一种新的方法 GlyR 亚型特异性的分子支架，该支架的最高点击次数为 10-100 倍。 比吗啡更有效地抑制炎症性疼痛，并且可以减轻疼痛。 达到相同镇痛水平所需的吗啡需要量增加 50 倍。 在该项目的筹备（UG3）阶段，我们将与 BPN 建立一个牵头开发团队 顾问并通过评估热门产品的功效来巩固支架的临床价值 然后我们将进入药物发现（UH3）阶段以完成治疗神经性疼痛。 通过以下三个具体目标进行命中先导优化：（1）最大化效力和 通过 (a) 计算机 SAR 探索新命中的功效，以改善 ADMET 概况和 优化结合亲和力，(b) 由 BPN 承包商合成设计的类似物，以及 (c) 使用电生理学作为主要测定法在体外评估合成的类似物 使用啮齿动物炎症和神经性疼痛模型作为辅助测定的体内 (2) 进行。 针对顶级类似物的 ADMET 检测，重点关注生物利用度分析、脑到血浆 分布、微粒体稳定性、血浆蛋白结合、细胞色素 P450 (CYP) 诱导和 肝脏、脾脏、血液、肺、 (3) 通过 α3- 体内疼痛模型测量建立特异性。 GlyR 敲除小鼠使用具有良好 ADMET 特征的类似物来确认预期 反筛选对阿片受体、大麻素受体和的脱靶效应。 其他离子通道将通过精神活性药物筛选计划 (PDSP) 进行测量 我们的目标是确定一种单一先导化合物以供 FDA 研究性新药批准。 到 UH3 阶段结束时。