5‐HT2CR ALLOSTERIC MODULATORS AS NOVEL PHARMACOTHERAPY IN COCAINE USE DISORDER

 描述(申请人提供)：可卡因使用障碍在美国仍然是一个严重的健康问题，迫切需要有效和安全的药物治疗方法来最大限度地获得治疗成功，并将药物使用失误降至最低。可卡因使用障碍的循环过程与一系列行为和认知过程有关，其中冲动(对刺激的快速计划外反应，而不考虑后果)和线索反应(对与可卡因相关的线索的注意偏差)被认为是两种关键的表型，即使在康复数年后也容易复发。5-羟色胺(5-HT)系统提供对冲动性和线索反应性的调节控制，特别是通过G蛋白偶联的5-HT2C受体(5-HT2CR)。数据表明，抑制的5-HT2CR信号能力可能有助于复发的表型易感性，5-HT2CR音调的正常化可能有助于抑制由冲动和线索反应性促进的复发。我们推测，5-HT2CR的小分子正变构调节剂(PAM)可以增强对内源性5-HT2CR和/或外源性5-HT2CR正构配体的反应，是一种恢复5-HT2CR功能的新策略。目前的赠款是建立在我们在新化学实体的合理设计、合成和药理学评估方面的进展，基于唯一报道的选择性5-HT2CR PAM PNU-69176E。我们已经合成了新的小分子(例如，cyd-1-79、cyd-3-30、cyd-6-16-2)，它们的初始特征是5-HT2CR PAM(活细胞功能信号、放射性配基结合分析)和合理的口服和脑生物利用度。体内行为学研究表明，在不影响一般运动活动的剂量下，Cyd-1-79在药物辨别分析中增强了选择性5-HT2CR激动剂的效果，并抑制了大鼠的冲动和线索反应，表明了有效性。 在与可卡因使用障碍的复发相关的主要动物模型中。我们的目标是优化具有良好药物代谢和药代动力学(DMPK)特征的5-HT2CR PAM，并分析概念验证行为模型中的选定分子以支持可卡因使用障碍的治疗潜力。为了实现我们的目标，我们将：(1)设计、合成和优化5-HT2CR PAM；(2)确定5-HT2CR PAM的选择性、特异性和体外DMPK谱；(3)测定体内DMPK和优化的5-HT2CR PAM在啮齿动物冲动性和线索反应性模型中的有效性。这一创新的、潜在高影响的小分子开发项目将阐明有关5-HT2CR变构调节的化学神经生物学的重要新信息，并推动可卡因使用障碍和抗复发药物的新概念和方向。

 DESCRIPTION (provided by applicant): Cocaine use disorder remains a significant health problem in the United States, and effective and safe pharmacotherapeutic approaches are urgently needed to maximize treatment success and minimize lapses to drug use. The cycling course of cocaine use disorder is tied to a multitude of behavioral and cognitive processes with impulsivity (rapid unplanned reactions to stimuli without regard for the consequences) and cue reactivity (attentional bias toward cocaine-associated cues) cited as two key phenotypes that set up vulnerability to relapse even years into recovery. The serotonin (5-HT) system provides modulatory control over impulsivity and cue reactivity, particularly through the G protein-coupled 5-HT2C receptor (5-HT2CR). Data suggest that dampened 5- HT2CR signaling capacity may contribute to phenotypic vulnerability to relapse and that normalization of 5-HT2CR tone may be useful to suppress relapse promoted by impulsivity and cue reactivity. We hypothesize that a small molecule positive allosteric modulator (PAM) of the 5-HT2CR that augments the response to endogenous 5-HT and/or an exogenous 5-HT2CR orthosteric ligand is a novel strategy to restore 5-HT2CR function. The present grant is built upon our progress in the rational design, synthesis and pharmacological evaluation of new chemical entities based upon the only reported selective 5-HT2CR PAM PNU-69176E. We have synthesized new small molecules (e.g., CYD-1-79, CYD-3-30, CYD-6-16-2) which exhibit initial profiles as 5-HT2CR PAMs (functional signaling in live cells, radioligand binding assays) and reasonable oral and brain bioavailability. In vivo behavioral studies demonstrated that CYD-1-79, at doses that do not affect general motor activity, enhanced the effects of a selective 5-HT2CR agonist in drug discrimination analyses, and suppressed impulsivity and cue reactivity in rats, indicating efficacy in primary animal models pertinent to relapse in cocaine use disorder. Our objective is to optimize 5-HT2CR PAMs with a favorable drug metabolism and pharmacokinetics (DMPK) profile, and analyze select molecules in proof-of-concept behavioral models to support therapeutic potential for cocaine use disorder. To accomplish our objective, we will: (1) design, synthesize and optimize 5-HT2CR PAMs; (2) define selectivity and specificity and DMPK profiles of 5-HT2CR PAMs in vitro; and (3) determine DMPK in vivo and efficacy of optimized 5-HT2CR PAMs in rodent models of impulsivity and cue reactivity. This innovative, potentially high impact small molecule development project will elucidate important new information about the chemical neurobiology of 5-HT2CR allosteric modulation, and drive new concepts and directions in cocaine use disorder and anti-relapse medications.