Opioid use disorders: UF Pharmacy medications discovery and development

项目总结 本项目提交的资金机会公告(FOA)编号：RFA-DA-19-002。 阿片类药物被严重过量处方，并与许多人的死亡有关，导致 国家目前的阿片类药物危机。美国食品和药物管理局最近批准α2肾上腺素能激动剂洛非西定为非成瘾性药物， 非阿片类药物治疗阿片类药物使用障碍。这项临床前药物开发工作源于 具有精神活性的天然产品，三叶草，一种泰国草药，用于自我治疗 阿片类药物使用障碍。米拉吉宁是该植物中含量最丰富的生物碱，是一种低效的G-受体激动剂。 蛋白质信号偏向。我们的初步研究表明，米拉吉宁具有有限的滥用责任，并相互作用 与包括α-2肾上腺素能受体在内的非阿片类中枢神经系统靶点，这些受体尚未在其独特的 机制。一种能同时与阿片和α-2肾上腺素能受体相互作用的药物(米曲宁)将提供 治疗阿片类药物使用障碍的高度创新的方法。这里计划的工作，涉及一个协作的， 跨学科小组，将通过合成衍生品研究米特拉宁的药效成分 这一方法导致了对吗啡基本药效团的理解。我们将使用 化学合成与前药合成相结合，体外代谢稳定性、亲和力及药效分析， 行为分析预测受体机制(药物歧视)、滥用(自我给药)和 不良反应(呼吸抑制、耐受性和依赖性)和体内ADME测定。米拉吉宁 类似物有望产生具有包括阿片类药物在内的药理机制的创新化合物 和肾上腺素能活动。我们为确定米曲林的药用需求所做的努力将导致 用于设计新型阿片受体配体的模板；这将极大地提高相互作用的知识 这些具有阿片受体的结构新颖的化合物，并促进这些配体的发展 治疗阿片类药物使用障碍。为期两年的普遍定期审议第三阶段的具体目标如下。目标1：确定 通过缺失设计和类似物稳定性确定米曲宁类似物的阿片类药效要求 米拉吉宁前药。目的2：研究米曲宁类似物在药物辨别、自我给药和 呼吸测试。类似物表现出所需的代谢稳定性、生物利用度、血脑屏障穿透性、 结合特性和行为活性将在UH3阶段进一步研究如下。目标3： 建立全面的米曲林类似物和前药的体内ADME。目标4：评估米曲宁 耐受性、依赖性和戒断试验中的类似物和前药。该项目的成果将提供 更全面地了解推定的识别元素的化学要求 阿片受体和α-2肾上腺素能受体上的米曲宁相关配体。最终，米曲林的潜在用途 并将实现其类似物作为开发阿片类药物使用障碍新疗法的模板 这可能会产生一种安全、有效的FDA批准的药物疗法。

PROJECT SUMMARY This project is submitted under Funding Opportunity Announcement (FOA) Number: RFA-DA-19-002. Opioids have been significantly over-prescribed and are associated with numerous deaths, resulting in the Nation’s current opioid crisis. The FDA recently approved the α2 adrenergic agonist lofexidine as a non-addictive, non-opioid treatment for opioid use disorder. This preclinical drug development effort stems from the psychoactive, natural product, Mitragyna speciosa (kratom), a Thai medicinal herb used as a self-treatment for opioid use disorder. Mitragynine, the plant’s most abundant alkaloid, is a low efficacy µ receptor agonist with G- protein signaling bias. Our preliminary studies suggest that mitragynine has limited abuse liability, and interacts with non-opioid CNS targets including α2 adrenergic receptors, which have not been exploited in its unique mechanism. A single drug (mitragynine) that interacts with both opioid and α2 adrenergic receptors would offer a highly innovative approach for treating opioid use disorder. The work planned here, involving a collaborative, interdisciplinary team, will examine the pharmacophoric elements of mitragynine through synthetic derivatives in an approach that led to the understanding of the essential pharmacophore of morphine. We will use a combination of chemical and prodrug synthesis, in vitro metabolic stability, affinity and efficacy analysis, behavioral assays predictive of receptor mechanism (drug discrimination), abuse (self-administration), and untoward effects (respiratory depression, tolerance, and dependence), and in vivo ADME assays. Mitragynine analogs are expected to yield innovative compounds with a pharmacological mechanism that includes opioid and adrenergic activity. Our efforts to identify the pharmacophoric requirements of mitragynine will lead to templates for the design of novel opioid receptor ligands; this will greatly improve the knowledge of interactions of these structurally novel compounds with opioid receptors and facilitate the development of these ligands as treatments for opioid use disorders. The specific aims of the 2-year UG3 phase are as follows. AIM 1: Identify opioid pharmacophoric requirements of mitragynine analogs through deletion design and analog stability; identify mitragynine prodrugs. AIM 2: Investigate mitragynine analogs in drug discrimination, self-administration, and respiration assays. Analogs exhibiting desired metabolic stability, bioavailability, blood-brain-barrier penetration, binding characteristics, and behavioral activity will be further studied in the UH3 phase as follows. AIM 3: Establish comprehensive in vivo ADME of mitragynine analogs and prodrugs. AIM 4: Assess mitragynine analogs and prodrugs in tolerance, dependence, and withdrawal assays. The results of this project will provide a more comprehensive understanding of the chemical requirements of the putative recognition elements of mitragynine-related ligands at opioid and α2 adrenergic receptors. Ultimately, the potential use of mitragynine and its analogs as templates for the development of a new treatment for opioid use disorders will be realized that may have the potential to yield a safe, effective FDA-approved pharmacotherapy.