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

基本信息

批准号：
10312823
负责人：
Christopher R McCurdy
金额：
$ 144.47万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
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/10312823
关键词：
Acclimatization Address Adrenergic Agents Adrenergic Agonists Adrenergic Receptor Affinity Agonist Alkaloids Attenuated Behavioral Behavioral Assay Binding Binding Proteins Biological Assay Biological Availability Blood - brain barrier anatomy Brain Cell Line Cessation of life Characteristics Chemicals Chronic Clonidine Data Dependence Development Dose Drug Kinetics Drug usage Elements Exhibits FDA approved Female Frequencies Funding Funding Opportunities GTP-Binding Proteins Half-Life Hepatocyte Human Hyperventilation In Vitro Individual Investigation Knowledge Lead Ligand Binding Ligands Liver Microsomes Measures Medicinal Herbs Metabolic Methadone Microsomes Mitragyna Morphine Naltrexone Natural Products Opiate Addiction Opioid Opioid Receptor Opioid agonist Oral Overdose Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacotherapy Pharmacy facility Phase Plants Plasma Plasma Proteins Preclinical Drug Development Prodrugs Property Rattus Receptor Activation Renal clearance function Respiration Schedule Self Administration Signaling Protein Stimulus Testing Therapeutic Tissues United States Ventilatory Depression Withdrawal Work abuse liability analog antagonist blood-brain barrier penetration design drug discovery drug discrimination efficacy evaluation improved in vivo innovation lofexidine male metabolic abnormality assessment mu opioid receptors mu receptors non-opioid analgesic novel novel strategies novel therapeutics opioid abuse opioid epidemic opioid use opioid use disorder pharmacophore predictive test prevent radioligand receptor respiratory scale up stem

项目摘要

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.

项目摘要该项目根据资金机会公告（FOA）编号提交：RFA-DA-19-002。阿片类药物已被明显过多处方，并与许多死亡有关，导致国家目前的阿片类药物危机。 FDA最近批准了α2肾上腺素能激动剂lofexidine是一种非添加性的，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从精神活性，天然产品，mitragyna speciosa（kratom），一种泰国医学草药，用作自我处理 OOPIOED使用障碍。 Mitragynine是该植物最丰富的生物碱，是一种低效率µ受体激动剂，具有G- 蛋白质信号偏置。我们的初步研究表明，Mitragynine的虐待责任有限，并且互动与包括α2肾上腺素受体在内的非阿片类CNS靶标，尚未以其独特的方式探索机制。一种与阿片类药物和α2肾上腺素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方法。在这里计划的工作涉及一项合作，跨学科团队将通过合成衍生物在一种导致理解吗啡基本药丸的方法。我们将使用一个化学和前药合成的结合，体外代谢稳定性，亲和力和效率分析，行为测定预测受体机制（药物歧视），滥用（自我管理）和不良影响（呼吸抑郁，耐受性和依赖性）和体内ADME分析。 mitragynine 预计类似物将通过包括阿片类药物在内的药物机制产生创新化合物和肾上腺素活性。我们确定Mitragynine的药学要求的努力将导致新型阿片受体配体设计的模板；这将大大提高互动知识在这些结构新颖的化合物中，阿片受体，并促进这些配体的发展卵毒素使用障碍的治疗方法。 2年UG3阶段的具体目的如下。目标1：识别通过缺失设计和模拟稳定性，mitragynine类似物对阿片类药物的要求；确认 mitragynine前药。目标2：研究药物歧视，自我管理和呼吸测定。表现出所需代谢稳定性，生物利用度，血脑屏障渗透的类似物，结合特征和行为活性将在UH3阶段进一步研究，如下所示。目标3：建立Mitragynine类似物和前药的全体体内疗程。目标4：评估Mitragynine 耐受性，依赖性和撤回测定法的类似物和前药。该项目的结果将提供对推定识别元素的化学要求的更全面的理解阿片类药物和α2肾上腺素受体的Mitragynine相关配体。最终，Mitragynine的潜在用途它的类似物作为用于开发阿片类药物使用障碍的新方法的模板这可能有可能产生安全，有效的FDA批准药物疗法。