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 阿片类药物使用障碍（OUD）在过去几十年中已经发展到流行病的程度，影响了数百万人 每年造成成千上万人死亡。虽然药物治疗是 为了治疗OUD，目前的治疗剂作用于μ阿片受体（莫尔）本身。莫尔激动剂 具有高的误用风险，因此它们的施用必须严格控制，而莫尔拮抗剂 在治疗开始前需要有一个受监督的停药期。这些要求创造了 严重阻碍寻求治疗的OUD患者获得治疗。另一种策略是， OUD的治疗是靶向介导成瘾的除莫尔以外的受体。其中一个目标是 5-羟色胺2C（5-HT 2C）受体，其对中脑边缘多巴胺能信号传导施加紧张性抑制， 这是大脑对刺激（如滥用药物）的奖励反应的基础。临床前数据 经验证的5-HT 2C激动作用是治疗可卡因、酒精和尼古丁成瘾的有效手段。 虽然研究较少，但最近的临床前研究支持5-HT 2C的疗效 对阿片类药物成瘾的激动作用。在我们研究育亨宾天然代谢物的过程中， 产品，我们已经设计并合成了一个先导化合物表现出5-HT 2C的激动剂。的 我的提案的目的是进一步开发一种有效的，有偏见的，有选择性的小分子5- HT 2C激动剂，随后在阿片类药物成瘾动物模型中进行疗效研究。合成我们的类似物 先导化合物将通过计算分子对接来引导，并通过体外功能性分析来通知 效价、偏倚和选择性的测定，以及顶级类似物将进入药代动力学， 毒性测试然后，选择的类似物将被推进到体内功效研究中，使用药物诱导的免疫抑制剂。 小鼠中的条件性位置偏好测定。该研究培训计划包括药物 化学、有机合成、计算建模、化学生物学、神经科学和体内分析 技术.它将作为西北大学和美国大学之间合作努力的一部分， 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.