Delineating the role of serotonin 5-HT2 receptors in opioid use disorders:Development of novel 5-HT2 modulators with translational studies in rodents andprimates

描述血清素 5-HT2 受体在阿片类药物使用障碍中的作用：通过啮齿类动物和灵长类动物的转化研究开发新型 5-HT2 调节剂

• 批准号: 10164749
• 负责人: Raymond G. Booth
• 金额: $ 60.62万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164749
• 关键词: Address; Affinity; Agonist; Amines; Amino Acid Receptors; Attenuated; Behavior; Behavioral; Behavioral Mechanisms; Binding; Bioavailable; Buprenorphine; Cardiotoxicity; Clone Cells; Collaborations; Cues; Data; Development; Dopamine; Dose; Drug Addiction; Drug usage; Electrostatics; Epidemic; Equilibrium; Evaluation; Extinction (Psychology); Fentanyl; Food; Functional disorder; Future; G-Protein-Coupled Receptors; Goals; Head; Health Personnel; Heroin; Human; Hydrophobicity; In Vitro; Intervention; Juice; Laboratories; Lead; Ligands; Macaca mulatta; Mediating; Methadone; Methods; Modeling; Molecular; Molecular Conformation; Monkeys; Mutate; Naloxone; Opiate Addiction; Opioid; Opioid Analgesics; Oral; Overdose; Oxycodone; Palate; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Pharmacology Study; Pharmacotherapy; Primates; Procedures; Proteins; Protocols documentation; Rattus; Recombinants; Reinforcement Schedule; Relapse; Research; Rodent; Role; Safety; Saimiri; Saline; Schedule; Self Administration; Serotonergic System; Serotonin; Serotonin Syndrome; Signal Transduction; Structure; Substance Use Disorder; System; Testing; Time; Training; Translating; Yawning; addiction; analog; attenuation; base; behavior observation; behavioral economics; computational chemistry; design; drug discrimination; drug of abuse; drug seeking behavior; enantiomer; endogenous opioids; experience; illicit opioid; in vivo; interest; medication safety; mesolimbic system; molecular modeling; non-opioid analgesic; nonhuman primate; novel; opioid abuse; opioid use disorder; overdose death; prescription opioid; prescription opioid abuse; programs; public health emergency; receptor; reinforced behavior; relapse risk; relating to nervous system; sedative; small molecule; social stigma; stereochemistry; translational study

This application responds to PA-18-058 to address the epidemic levels of prescription opioid abuse and addiction that have resulted in an appalling number of overdose deaths. Unequivocally, there is an urgent need for effective pharmacologic treatment options for opioid use disorder (OUD) that are safe, non-addictive, and without substantial diversion liability to address the national public health emergency. Compelling evidence suggests that serotonin (5HT) 2A and 2C G protein-coupled receptor (GPCR) subtypes may provide a fruitful strategy to achieve this goal. In this regard, 5HT2C agonists can reduce self-administration and block relapse-related drug- seeking behavior in rodents and monkeys. This has prompted development of 5HT2C-specific agonists that are devoid of potentially deleterious effects mediated through activation of the 5HT2A (i.e., hallucinogenic) and 5HT2B (i.e., cardiotoxic) subtypes. Furthermore, 5HT2C-specific agonists are required to delineate the roles of 5HT2 receptor subtypes in substance use disorders. To this end, our medicinal chemistry program has produced 4- phenyl-2-aminotetralin (PAT) analogs with unique multifunctional pharmacology at 5HT2 GPCRs, i.e., activation of 5HT2C signaling with inactivation of 5HT2A and 5HT2B signaling in the same monovalent, orally bioavailable, small molecule. Our preliminary results indicate the unique PAT-type 5HT2 pharmacology translates effectively in models of OUD in rhesus monkeys, including, attenuation of heroin-primed reinstatement, suggesting efficacy for addressing relapse. PATs do not have stimulant or sedative effects and are without liability for addiction, encouraging us to pursue translational studies in nonhuman primates (NHP) to guide development of PAT-type 5HT2 modulators as pharmacologic intervention for prescription and illicit opioid abuse, as well as, delineate 5HT2 roles in OUD. The overarching hypothesis tested is that an optimal balance of PAT function at 5HT2A receptors (inverse agonism/antagonism, partial agonism) relative to agonist function at 5HT2C receptors (implicit is no activation of 5HT2B) translates to beneficial effects in primate models of OUD. In Aim 1A medicinal chemistry and Aim 1B molecular pharmacology studies we will develop PAT analogs with a range of functional activities, potencies, and efficacies at 5HT2 receptors, including 5HT2C-specific agonists with 5HT2A inverse agonism. In Aim 2A we will assess the PATs for in vivo potency and efficacy at 5HT2A and 5HT2C receptors to establish dosing parameters for NHP studies. Aim 2B studies will use drug discrimination studies to evaluate in vivo 5HT2 activity in squirrel monkeys. Aim 3 will assess PATs for safety and efficacy to attenuate oxycodone and fentanyl self-administration as well as drug- and cue-primed reinstatement in squirrel monkeys. Results will establish the role of serotonergic 5HT2 receptors in the pathophysiology and pharmacotherapy of OUD. PATs that selectively block responding for drug self-administration and have appropriate safety and efficacy parameters including with regard to relapse will be considered for development in collateral future studies in collaboration with an identified interested pharma.

该申请响应PA-18-058，以解决处方滥用和成瘾的流行水平 这导致了大量的过量死亡。明确地，迫切需要有效 阿片类药物使用障碍（OUD）的药理学治疗方案，安全，非依恋，没有 实质性转移责任以解决国家公共卫生紧急情况。令人信服的证据表明 5-羟色胺（5HT）2A和2C G蛋白偶联受体（GPCR）亚型可能为您提供富有成果的策略 实现这一目标。在这方面，5HT2C激动剂可以减少自我给药，并阻止与复发相关的药物 寻求啮齿动物和猴子的行为。这引发了5HT2C特异性激动剂的发展 没有通过5HT2A（即致幻剂）和5HT2B激活介导的潜在有害效应 （即心脏毒性）亚型。此外，需要5HT2C特异性激动剂来描述5HT2的角色 药物使用障碍中的受体亚型。为此，我们的药物化学计划已产生4-- 在5HT2 GPCR上具有独特多功能药理学的苯基-2-氨基环蛋白（PAT）类似物，即激活 5HT2C信号传导的5HT2A和5HT2B信号传导的信号传导，同一单价，口服生物利用 小分子。我们的初步结果表明独特的PATTYPE 5HT2药理学有效地翻译 在恒河猴中的Oud模型中，包括恢复海洛因的衰减 用于解决复发。 PATS没有刺激性或镇静作用，并且对成瘾不承担任何责任， 鼓励我们在非人类灵长类动物（NHP）中进行翻译研究，以指导Pat-Type的开发 5HT2调节剂作为处方和非法阿片类药物滥用的药理干预措施，以及划定 5HT2在Oud中的角色。所测试的总体假设是PAT功能在5HT2A处的最佳平衡 相对于5HT2C受体的激动剂功能，受体（反向激动剂/拮抗，部分激动剂）（隐式） 5HT2B的激活不转化为在Oud的灵长类动物模型中的有益效果。在AIM 1A药物化学中 AIM 1B分子药理学研究我们将开发具有一系列功能活动的PAT类似物， 5HT2受体的效力和功效，包括5HT2C特异性激动剂，具有5HT2A反向激动剂。在 AIM 2A我们将评估5HT2A和5HT2C受体的体内效力和功效的PATS建立 NHP研究的剂量参数。 AIM 2B研究将使用药物歧视研究来评估体内5HT2 松鼠猴子的活动。 AIM 3将评估PATS的安全性和功效，以减轻羟考酮和芬太尼 在松鼠猴子中的自我管理以及毒品和提示剂的恢复原状。结果将确定 血清素能5HT2受体在OUD的病理生理学和药物疗法中的作用。有选择地拍拍 对药物自我给药的响应，并具有适当的安全性和效力参数 关于复发，将考虑与确定的 有兴趣的药物。