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

5-HT2CR 变构调节剂作为可卡因使用障碍的新型药物治疗

• 批准号: 9271312
• 负责人: Kathryn A. Cunningham
• 金额: $ 0.89万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9271312
• 关键词: Address; Affect; Affinity; Agonist; Allosteric Site; Animal Model; Behavior; Behavioral; Behavioral Model; Binding; Biological Assay; Biological Availability; Brain; Categories; Cells; Cellular Assay; Chemicals; Cocaine; Coupled; Cues; Data; Dependence; Development; Disease; Dose; Drug Kinetics; Drug usage; Engineering; Ensure; Evaluation; Exhibits; Family member; GTP-Binding Proteins; Genetic; Goals; Grant; Head; Health; Impulsivity; In Vitro; Investigation; Knowledge; Legal patent; Life; Ligands; Medial; Mediating; Medical; Mental disorders; Methods; Mission; Modeling; Motor Activity; Neurobiology; Obesity; Oral; Patients; Penetration; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Prefrontal Cortex; Public Health; Radioligand Assay; Rattus; Reaction; Receptor Signaling; Recovery; Relapse; Reporting; Research; Research Project Grants; Rodent Model; Serotonin; Serotonin Receptor 5-HT2C; Sexual Dysfunction; Signal Transduction; Site; Specificity; Stimulus; System; Tail; Therapeutic; Translational Research; Treatment Efficacy; United States; United States National Institutes of Health; Urinary Incontinence; Validation; addiction; attentional bias; base; behavioral study; burden of illness; clinical application; cocaine use; cognitive process; cue reactivity; design; drug discrimination; drug metabolism; improved; in vivo; innovation; multidisciplinary; novel; novel strategies; novel therapeutics; positive allosteric modulator; pre-clinical; programs; protein expression; psychologic; radioligand; receptor; receptor function; relating to nervous system; research study; response; scaffold; small molecule; success

 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.

 描述（由申请人提供）：可卡因使用障碍在美国仍然是一个重大的健康问题，迫切需要有效且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滥用。可卡因使用障碍的循环过程与多种行为和认知过程有关，其中包括冲动（对刺激的快速、无计划的反应，不考虑后果）和线索反应性（对可卡因相关线索的注意偏差），被认为是两个关键表型，即使在康复数年后也容易复发。血清素 (5-HT) 系统对冲动性和提示反应性提供调节控制，特别是通过 G 蛋白偶联的 5-HT2C 受体 (5-HT2CR)。数据表明，减弱的 5-HT2CR 信号传递能力可能导致表型易复发，并且 5-HT2CR 音调正常化可能有助于抑制冲动和提示反应性促进的复发。我们假设 5-HT2CR 的小分子正变构调节剂 (PAM) 增强对内源 5-HT 和/或外源 5-HT2CR 正位配体的反应，是恢复 5-HT2CR 功能的新策略。目前的资助是基于我们基于唯一报道的选择性 5-HT2CR PAM PNU-69176E 在新化学实体的合理设计、合成和药理学评估方面取得的进展。我们合成了新的小分子（例如 CYD-1-79、CYD-3-30、CYD-6-16-2），其表现出 5-HT2CR PAM 的初始特征（活细胞中的功能信号传导、放射性配体结合测定）以及合理的口服和大脑生物利用度。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，增强了药物辨别分析中选择性 5-HT2CR 激动剂的作用，并抑制了大鼠的冲动和提示反应性，表明了功效 在与可卡因使用障碍复发相关的主要动物模型中。我们的目标是优化 5-HT2CR PAM，使其具有良好的药物代谢和药代动力学 (DMPK) 特征，并在概念验证行为模型中分析选定的分子，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-HT2CR PAM； (2) 定义 5-HT2CR PAM 的体外选择性和特异性以及 DMPK 特征； (3) 确定体内 DMPK 以及优化的 5-HT2CR PAM 在啮齿动物冲动和提示反应性模型中的功效。这一创新的、具有潜在高影响力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。