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.

美国三分之一的人口患有慢性疼痛，但现有的治疗方案 是不够的。阿片类止痛药的过度使用导致了目前的阿片类药物流行 危机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 非阿片类强效止痛药利用人体的高分辨率结构 甘氨酸受体（hGlyRs），我们发现了一个独特的跨膜药物结合位点， 负责介导大麻的非精神活性镇痛作用的结构域。 使用创新的基于整体的虚拟筛选方法来针对这个独特的网站， 随后进行功能调节的体外电生理学测量和体内电生理学测量。 在小鼠炎症性疼痛模型的疼痛治疗测量中，我们发现了一种新的 GlyR亚型特异性的分子支架。这个脚手架的最高点击率是10-100倍 比吗啡更有效地抑制炎性疼痛。此外，最高命中率可以减少 吗啡需求量的50倍，以达到相同的镇痛水平。在 在该项目的预备（UG 3）阶段，我们将与BPN建立一个领先的开发团队 顾问和巩固支架的临床价值，通过评估疗效的顶部命中， 治疗神经性疼痛。然后，我们将进入药物发现（UH 3）阶段， 通过以下三个具体目标进行命中-领先优化：（1）最大化效力， 通过（a）计算机模拟SAR探索改善ADMET特征和 优化结合亲和力，（B）通过BPN承包商合成所设计的类似物，和（c） 使用电生理学作为主要测定法在体外评价合成的类似物， 使用啮齿动物炎性和神经性疼痛模型作为二级测定。(2)执行 用于顶级类似物的ADMET检测，重点关注生物利用度分析，脑至血浆 分布、微粒体稳定性、血浆蛋白结合、细胞色素P450（CYP 1A 1）诱导和 抑制、艾姆斯活性和流式细胞术检测肝、脾、血、肺 肾脏和大脑(3)通过体内疼痛模型测量α3- GlyR敲除小鼠使用具有有利ADMET特征的类似物来确认预期的 目标对阿片受体、大麻素受体和阿片受体的脱靶效应的反筛选 其他离子通道将由精神活性药物筛选计划（PDSP）测量， NIMH。我们的目标是确定一个单一的先导化合物的FDA研究新药批准 到UH 3阶段结束时。