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: 10410391
• 负责人: Raymond G. Booth
• 金额: $ 61.31万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10410391
• 关键词: Address; Affinity; Agonist; Amines; Amino Acid Receptors; Attenuated; Behavior; Behavioral; Behavioral Mechanisms; Binding; 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 reversal; 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; Stimulant; Structure; Substance Use Disorder; System; Testing; Time; Training; Translating; Yawning; addiction; addiction liability; analog; antagonist; 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.

该应用程序响应 PA-18-058，以解决处方阿片类药物滥用和成瘾的流行程度 这导致了令人震惊的服药过量死亡人数。毫无疑问，迫切需要有效的 阿片类药物使用障碍 (OUD) 的药物治疗选择安全、非成瘾且无副作用 为解决国家突发公共卫生事件而承担的重大转移责任。令人信服的证据表明 血清素 (5HT) 2A 和 2C G 蛋白偶联受体 (GPCR) 亚型可能提供一种富有成效的策略 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药物相关的复发 寻找啮齿动物和猴子的行为。这促进了 5HT2C 特异性激动剂的开发 没有通过激活 5HT2A（即致幻性）和 5HT2B 介导的潜在有害作用 （即心脏毒性）亚型。此外，需要 5HT2C 特异性激动剂来描述 5HT2 的作用 物质使用障碍中的受体亚型。为此，我们的药物化学项目已经产生了 4- 苯基-2-氨基四氢化萘 (PAT) 类似物在 5HT2 GPCR 中具有独特的多功能药理学，即激活 5HT2C 信号传导与 5HT2A 和 5HT2B 信号传导灭活相同的单价口服生物利用度， 小分子。我们的初步结果表明独特的 PAT 型 5HT2 药理学有效转化 在恒河猴 OUD 模型中，包括海洛因引发的恢复减弱，表明疗效 用于解决复发问题。 PAT 不具有兴奋或镇静作用，并且不会导致成瘾， 鼓励我们在非人类灵长类动物 (NHP) 中进行转化研究，以指导 PAT 型的开发 5HT2 调节剂作为处方药和非法阿片类药物滥用的药物干预，以及描绘 5HT2 在 OUD 中的作用。测试的总体假设是 5HT2A 时 PAT 功能的最佳平衡 受体（反向激动/拮抗、部分激动）相对于 5HT2C 受体激动剂功能（隐式 没有激活 5HT2B）转化为 OUD 灵长类动物模型的有益效果。目标 1A 药物化学 和目标 1B 分子药理学研究，我们将开发具有一系列功能活性的 PAT 类似物， 5HT2 受体的效力和功效，包括具有 5HT2A 反向激动作用的 5HT2C 特异性激动剂。在 目标 2A 我们将评估 PAT 对 5HT2A 和 5HT2C 受体的体内效力和功效，以确定 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 松鼠猴的活动。目标 3 将评估 PAT 的安全性和减弱羟考酮和芬太尼作用的有效性 松鼠猴的自我给药以及药物和提示引发的恢复。结果将确定 血清素能 5HT2 受体在 OUD 的病理生理学和药物治疗中的作用。有选择地进行 PAT 阻断药物自我给药的反应，并具有适当的安全性和有效性参数，包括 将考虑与已确定的机构合作，在未来的并行研究中发展关于复发的问题 有兴趣的制药公司。