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

 描述（由申请人提供）：在美国，可卡因使用障碍仍然是一个重大的健康问题，迫切需要有效和安全的药物治疗方法，以最大限度地提高治疗成功率，并最大限度地减少药物使用失误。可卡因使用障碍的循环过程与众多的行为和认知过程有关，其中冲动性（对刺激的快速无计划反应，而不考虑后果）和线索反应性（对可卡因相关线索的注意力偏差）被认为是两种关键的表型，这两种表型导致了即使在恢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-HT 2C受体（5-HT 2CR）。数据表明，抑制5-HT 2CR信号传导能力可能有助于复发的表型脆弱性和5-HT 2CR张力的正常化可能是有用的，以抑制复发促进冲动和线索反应。我们假设，5-HT 2CR的小分子正变构调节剂（PAM），增强对内源性5-HT和/或外源性5-HT 2CR正构配体的反应，是一种新的策略，以恢复5-HT 2CR功能。目前的资助是建立在我们的进展，在合理的设计，合成和药理学评价的新的化学实体的基础上，唯一报告的选择性5-HT 2CR PAM PNU-69176 E。我们已经合成了新的小分子（例如，CYD-1-79、CYD-3-30、CYD-6-16-2），其表现出作为5-HT 2CR PAM（活细胞中的功能性信号传导，放射性配体结合测定）的初始特征和合理的口服和脑生物利用度。体内行为研究表明，CYD-1-79在不影响一般运动活动的剂量下，在药物辨别分析中增强了选择性5-HT 2CR激动剂的作用，并抑制了大鼠的冲动性和线索反应性，表明其功效 在与可卡因使用障碍复发相关的初级动物模型中。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-HT 2CR PAM，并在概念验证行为模型中分析选择的分子，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-HT 2CR PAM;（2）在体外确定5-HT 2CR PAM的选择性和特异性以及DMPK谱;以及（3）在冲动和线索反应性的啮齿动物模型中确定体内DMPK以及优化的5-HT 2CR PAM的功效。这个创新的，潜在的高影响力的小分子开发项目将阐明有关5-HT 2CR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.