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

三分之一的美国人口患有慢性疼痛，但现有的治疗方案 是不够的。阿片类止痛药的过度使用助长了目前的阿片类药物流行。 危机。在这个蓝图神经治疗网络的应用中，我们提出了一种新颖的 强效非阿片类止痛药的临床应用。利用人体的高分辨率结构 甘氨酸受体(HGlyRs)，我们在跨膜上发现了一个独特的药物结合部位 负责调节大麻的非精神活性止痛作用的领域。 使用一种创新的基于整体的虚拟筛选方法来瞄准这个独特的网站， 随后进行了功能调节的体外电生理学测定和体内电生理测定 在小鼠炎症性疼痛模型中对疼痛治疗的测量，我们发现了一种新的 具有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次 在抑制炎性疼痛方面比吗啡更有效。此外，最热门的点击量可以减少 将吗啡用量提高50倍才能达到同等水平的止痛效果。在 这个项目的准备(UG3)阶段，我们将与BPN建立一个领先的开发团队 咨询和巩固支架的临床价值，通过评估在 治疗神经病理性疼痛。然后我们将进入药物发现(UH3)阶段，以完成 通过以下三个具体目标实现从点击到领先的优化：(1)最大限度地提高效率和 通过(A)在硅胶合成孔径雷达勘探中改善ADMET剖面和 优化结合亲和力，(B)合成BPN承包商设计的类似物，以及(C) 以电生理学为主要指标对合成的类似物进行体外评价 在体用啮齿类动物炎症和神经病理性疼痛模型作为二次检测。(2)表演 ADMET对顶级类似物的分析，重点是生物利用度分析、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、脾、血、肺中毒性标志物的抑制、Ames活性和流式细胞术， 肾脏和大脑。(3)通过α3-体内疼痛模型的测量建立特异性 GlyR基因敲除小鼠使用具有良好ADMET图谱的类似物来确认预期的 目标。阿片受体、大麻素受体和阿片受体脱靶效应的反筛选 其他离子通道将由精神活性药物筛选计划(PDSP)在 尼姆。我们的目标是为FDA试验性新药批准确定一种单一的先导化合物 到UH3阶段结束时。

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.