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: 10525226
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10525226
• 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 Interactions; 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; 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; medication for opioid use disorder; metabolic abnormality assessment; non-opioid analgesic; novel; novel strategies; novel therapeutics; opioid abuse; opioid epidemic; opioid use; opioid use disorder; pharmacologic; pharmacophore; predictive test; prevent; radioligand; receptor; respiratory; scale up; 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.

项目概要 该项目根据资助机会公告 (FOA) 提交，编号：RFA-DA-19-002。 阿片类药物的处方量严重过量，导致大量死亡，导致 美国当前的阿片类药物危机 FDA 最近批准了 α2 肾上腺素激动剂洛非西定作为一种非成瘾性药物。 该临床前药物开发工作源于阿片类药物使用障碍的非阿片类药物治疗。 具有精神活性的天然产品 Mitragyna spiosa（kratom），一种泰国草药，用于自我治疗 阿片类药物使用障碍。帽柱木碱是植物中最丰富的生物碱，是一种低效的 G-受体激动剂。 我们的初步研究表明帽柱木碱的滥用可能性和相互作用有限。 非阿片类中枢神经系统靶点，包括 α2 肾上腺素能受体，该受体尚未以其独特的方式得到利用 与阿片类药物和 α2 肾上腺素能受体相互作用的单一药物（帽柱木碱）将提供这种机制。 这里计划的工作涉及一种高度创新的治疗阿片类药物使用障碍的方法，涉及协作、 跨学科团队将通过合成衍生物检查帽柱木碱的药效成分 我们将使用一种方法来了解吗啡的基本药效团。 化学和前药合成的结合，体外代谢稳定性，亲和力和功效分析， 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。 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 我们努力确定帽柱木碱的药效要求将导致： 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 这些结构新颖的化合物与阿片受体的结合，并促进这些配体的开发 2 年 UG3 阶段的具体目标如下： 识别阿片类药物使用障碍。 通过缺失设计和类似物稳定性鉴定帽柱木碱类似物的阿片类药效团要求； 目的 2：研究帽柱木碱类似物在药物辨别、自我给药和治疗中的作用。 呼吸测定类似物表现出所需的代谢稳定性、生物利用度、血脑屏障渗透性， 结合特征和行为活性将在 UH3 阶段进一步研究如下： 建立帽柱木碱类似物和前药的全面体内 ADME 目标 4：评估帽柱木碱。 该项目的结果将提供类似物和前药在耐受性、依赖性和戒断方面的分析。 更全面地了解假定的识别元素的化学要求 阿片类药物和α2肾上腺素受体的帽柱木碱相关配体最终是帽柱木碱的潜在用途。 及其类似物作为开发阿片类药物使用障碍新疗法的模板将成为现实 这可能有潜力产生一种安全、有效的 FDA 批准的药物疗法。

项目成果

Evaluation of the rewarding effects of mitragynine and 7-hydroxymitragynine in an intracranial self-stimulation procedure in male and female rats.

评估帽柱木碱和 7-羟基帽柱木碱在雄性和雌性大鼠颅内自我刺激过程中的奖励作用。

• 发表时间: 2020
• 影响因子: 4.2
• 作者: Behnood;Chellian, Ranjithkumar;Wilson, Ryann;Hiranita, Takato;Sharma, Abhisheak;Leon, Francisco;McCurdy, Christopher R;McMahon, Lance R;Bruijnzeel, Adriaan W
• 通讯作者: Bruijnzeel, Adriaan W

Kratom Alkaloids: A Blueprint?

卡痛生物碱：蓝图？

• 发表时间: 2023-01-18
• 影响因子: 5
• 作者: Smith, Kirsten Elin;Sharma, Abhisheak;Grundmann, Oliver;McCurdy, Christopher R
• 通讯作者: McCurdy, Christopher R

Tolerance and dependence to Δ9-tetrahydrocannabinol in rhesus monkeys: Activity assessments.

恒河猴对α9-四氢大麻酚的耐受性和依赖性：活性评估。

• 发表时间: 2019
• 影响因子: 3.7
• 作者: Wilkerson, Jenny L;Schulze, David R;McMahon, Lance R
• 通讯作者: McMahon, Lance R

The effects of mitragynine and morphine on schedule-controlled responding and antinociception in rats.

帽柱木碱和吗啡对大鼠日程控制反应和抗伤害的影响。

• 发表时间: 2019-09
• 影响因子: 3.4
• 作者: Hiranita, Takato;Leon, Francisco;Felix, Jasmine S;Restrepo, Luis F;Reeves, Morgan E;Pennington, Anna E;Obeng, Samuel;Avery, Bonnie A;McCurdy, Christopher R;McMahon, Lance R;Wilkerson, Jenny L
• 通讯作者: Wilkerson, Jenny L

Characterization of a mouse neuropathic pain model caused by the highly active antiviral therapy (HAART) Stavudine.

由高活性抗病毒疗法（HAART）司他夫定引起的小鼠神经性疼痛模型的表征。

• 发表时间: 2021-10
• 作者: Wilkerson, Jenny L;Felix, Jasmine S;Bilbrey, Joshua A;McCurdy, Christopher R;McMahon, Lance R
• 通讯作者: McMahon, Lance R