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

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 导致了惊人数量的吸毒过量死亡毫无疑问，迫切需要有效的 阿片类药物使用障碍（OUD）的药物治疗选择是安全的，非成瘾性的， 应对国家突发公共卫生事件的重大转移责任。令人信服的证据表明 5-羟色胺（5-HT）2A和2C G蛋白偶联受体（GPCR）亚型可能提供了一种富有成效的策略， 实现这一目标。在这方面，5 HT 2C激动剂可以减少自我给药，并阻断复发相关的药物。 在啮齿动物和猴子中寻找行为。这促进了5 HT 2C特异性激动剂的开发， 没有通过激活5 HT 2A介导的潜在有害作用（即，致幻）和5 HT 2B (i.e.,心脏毒性）亚型。此外，需要5 HT 2C特异性激动剂来描述5 HT 2的作用。 物质使用障碍中的受体亚型。为此，我们的药物化学计划产生了4- 苯基-2-氨基四氢化萘（PAT）类似物在5 HT 2 GPCR处具有独特的多功能药理学，即，激活 5 HT 2C信号传导与5 HT 2A和5 HT 2B信号传导的失活在相同的单价，口服生物可利用， 小分子。我们的初步结果表明，独特的PAT型5 HT 2药理学有效地转化为 在恒河猴OUD模型中，包括海洛因引发的恢复减弱，表明疗效 来解决复发的问题PAT不具有兴奋剂或镇静作用，并且没有成瘾的责任， 鼓励我们在非人灵长类动物（NHP）中进行转化研究，以指导PAT型的发展 5-HT 2调节剂作为处方和非法阿片类药物滥用的药物干预，以及描述 5 HT 2在OUD中的作用。测试的总体假设是PAT功能在5 HT 2A的最佳平衡 受体（反向激动/拮抗，部分激动）相对于5 HT 2C受体（隐含）的激动剂功能 没有激活5 HT 2B）在OUD的灵长类动物模型中转化为有益效果。目标1A药物化学 和Aim 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， 效力和对5 HT 2受体的效力，包括具有5 HT 2A反向激动作用的5 HT 2C特异性激动剂。在 目的2A我们将评估PAT对5 HT 2A和5 HT 2C受体的体内效力和功效，以建立 NHP研究的给药参数。目的2B研究将使用药物辨别研究来评估体内5 HT 2 松鼠猴的活动。目标3将评估PAT的安全性和有效性，以减少羟考酮和芬太尼 自我管理以及药物和线索引发的恢复松鼠猴。结果将确定 肾上腺素能5 HT 2受体在OUD的病理生理学和药物治疗中的作用。选择性地 阻断药物自我给药反应，并具有适当的安全性和有效性参数，包括 关于复发将考虑在未来的并行研究中与已确定的 感兴趣的制药公司

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.