Opioid use disorders: UF Pharmacy medications discovery and development

阿片类药物使用障碍：UF Pharmacy 药物的发现和开发

• 批准号: 10403754
• 负责人: Christopher R McCurdy
• 金额: $ 7.28万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10403754
• 关键词: Adrenergic Agents; Adrenergic Agonists; Adrenergic Receptor; Affinity; Agonist; Alkaloids; Behavioral; Behavioral Assay; Binding; Biological Assay; Biological Availability; Cessation of life; Characteristics; Chemicals; Dependence; Development; Elements; Exhibits; FDA approved; Funding Opportunities; GTP-Binding Proteins; In Vitro; Industry; Knowledge; Ligands; Medicinal Herbs; Metabolic; Mitragyna; Morphine; Natural Products; Opiate Addiction; Opioid; Opioid Receptor; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Pharmacy facility; Phase; Plants; Preclinical Drug Development; Privatization; Prodrugs; Respiration; Self Administration; Signaling Protein; Structure; Therapeutic; Ventilatory Depression; Withdrawal; Work; analog; blood-brain barrier penetration; design; drug development; drug discovery; drug discrimination; efficacy evaluation; improved; in vivo; innovation; lofexidine; mu receptors; non-opioid analgesic; novel; opioid epidemic; opioid use disorder; pharmacophore; predictive test; receptor; stem

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.

项目摘要 该项目是根据资助机会公告（FOA）编号：RFA-DA-19-002提交的。 阿片类药物被严重过量处方，并与许多死亡有关， 当前的鸦片危机FDA最近批准了α2肾上腺素能激动剂洛非西定作为一种非成瘾性， 阿片类药物使用障碍的非阿片类药物治疗。这种临床前药物开发工作源于 精神活性，天然产品，Mitragyna speciosa（kratom），一种泰国草药，用于自我治疗 阿片类药物使用障碍Mitragynine是植物中最丰富的生物碱，是一种低效率的µ受体激动剂，具有G- 蛋白质信号偏差我们的初步研究表明，mitragynine具有有限的滥用责任， 与非阿片类中枢神经系统的目标，包括α2肾上腺素能受体，这还没有被利用在其独特的 机制一种与阿片和α2肾上腺素能受体相互作用的单一药物（mitragynine）将提供 一种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，涉及一个合作， 跨学科的团队，将通过合成衍生物， 这一方法使我们了解了吗啡的基本药效团。我们将使用一个 化学和前药合成的组合，体外代谢稳定性，亲和力和功效分析， 预测受体机制（药物辨别）、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。紫穗槐碱 类似物有望产生具有药理机制的创新化合物， 和肾上腺素能活动。我们的努力，以确定药典要求的mitragynine将导致 设计新型阿片受体配体的模板;这将大大提高相互作用的知识 这些结构新颖的化合物与阿片受体，并促进这些配体的发展， 阿片类药物使用障碍的治疗。为期两年的UG 3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mitragynine类似物的阿片药理学要求;鉴定 mitragynine前药。目的2：研究mitragynine类似物在药物辨别、自我给药和 呼吸测定。具有所需代谢稳定性、生物利用度、血脑屏障穿透性 结合特性和行为活性将在UH 3阶段进一步研究如下。目标3： 建立米姜碱类似物和前药的全面体内ADME。目的4：评估米特拉宁 类似物和前药在耐受性、依赖性和戒断试验中的应用。该项目的成果将提供 更全面地了解假定的识别元件的化学要求， 阿片受体和α2肾上腺素能受体的mitragynine相关配体。最后，mitragynine的潜在用途 及其类似物作为开发阿片类药物使用障碍新治疗方法的模板， 这可能会产生一种安全有效的FDA批准的药物疗法。