The design, synthesis, and evaluation of natural product-inspired small molecules targeting the 5-HT2C receptor as novel therapeutics for opioid use disorder

项目摘要 在过去的几十年里，阿片类药物使用障碍(OUD)已经发展到流行的程度，影响了数百万人 每年造成数以万计的人死亡。虽然药物是一块基石 对于OUD的治疗，目前的治疗方法作用于MU阿片受体(MOR)本身。MOR激动剂 有很高的滥用风险，因此他们的管理必须受到严格的监管，而MOR拮抗剂 有必要在治疗开始前有一段时间在监督下停药。这些要求创造了 对于寻求治疗的OUD患者来说，获得治疗的障碍很大。一种替代战略，用于 OUD的治疗是针对介导成瘾的MOR以外的受体。一个这样的目标是 5-羟色胺2C(5-HT2C)受体对中脑边缘多巴胺能信号起紧张性抑制作用， 大脑对药物滥用等刺激做出奖赏反应的潜在途径。临床前数据显示 证实5-HT2C激动剂是治疗可卡因、酒精和尼古丁成瘾的有效手段。 尽管研究较少，但最近的临床前研究支持了5-HT2C的疗效 对抗阿片成瘾的激动剂也是。在我们研究天然育亨宾代谢物的过程中 产品方面，我们设计合成了一种具有5-HT2C激动剂活性的先导化合物。这个 我提议的目标是进一步开发一种有效的、有偏见的和选择性的小分子5- HT2C激动剂，随后在阿片成瘾动物模型中进行疗效研究。我们的类似物的合成 先导化合物将通过计算分子对接和体外功能信息来引导 效力、偏倚、选择性和顶级类似物的分析将进入药代动力学和 毒性测试。然后，选定的类似物将进入体内疗效研究，使用药物诱导的 小鼠条件性位置偏爱实验。这项研究培训计划包括医学 化学、有机合成、计算建模、化学生物学、神经科学和体内分析 技巧。它将作为西北大学合作努力的一部分进行 化学系和范伯格医学院转化神经药理学项目， 在外部合作者的进一步支持下。

Project Summary Opioid use disorder (OUD) has grown to epidemic proportions over the past few decades, affecting millions of Americans and contributing to tens of thousands of deaths each year. While medication is a cornerstone for the treatment of OUD, current therapeutics act upon the mu opioid receptor (MOR) itself. MOR agonists have a high risk of misuse and so their administration must be tightly regulated, while MOR antagonists necessitate a supervised withdrawal period before the beginning of treatment. These requirements create significant barriers to access for people with OUD who seek treatment. An alternative strategy for the treatment of OUD is to target receptors other than MOR which mediate addiction. One such target is the serotonin 2C (5-HT2C) receptor, which exerts tonic inhibition over mesolimbic dopaminergic signaling, the pathway underlying the brain's reward response to stimuli such as drugs of abuse. Preclinical data has validated 5-HT2C agonism as an effective means for treating addiction to cocaine, alcohol, and nicotine. Though less extensively investigated, recent preclinical studies have supported the efficacy of 5-HT2C agonism against opioid addiction as well. In the course of our studies of metabolites of yohimbine natural products, we have designed and synthesized a lead compound exhibiting agonism of 5-HT2C. The objective of my proposal is the further development of a potent, biased, and selective small molecule 5- HT2C agonist followed by efficacy studies in animal models for opioid addiction. Synthesis of analogs of our lead compound will be guided by computational molecular docking and informed by in vitro functional assays for potency, bias, and selectivity, and top analogs will be advanced into pharmacokinetic and toxicity testing. Selected analogs will then be advanced into in vivo efficacy studies, using a drug-induced Conditioned Place Preference assay in mice. This research training plan encompasses medicinal chemistry, organic synthesis, computational modeling, chemical biology, neuroscience, and in vivo assay techniques. It will be carried out as part of a collaborative effort between the Northwestern University Department of Chemistry and the Feinberg School of Medicine Translational Neuropharmacology Program, with further support from outside collaborators.