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（由适用提供）：在美国，可卡因使用障碍仍然是一个重大的健康问题，迫切需要采用有效且安全的药物治疗方法来最大程度地提高治疗成功并最大程度地减少吸毒的失误。可卡因使用障碍的循环过程与冲动性的多种行为和认知过程有关（对STIMULLI的快速外反应而不考虑后果）和提示反应性（引起可卡因相关的提示的注意力偏见）是两个关键的表型，这些表型可以恢复恢复。血清素（5-HT）系统提供了对冲动性和提示反应性的调节性控制，尤其是通过G蛋白偶联的5-HT2C受体（5-HT2CR）。数据表明，该死的5-HT2CR信号传导能力可能有助于表型易受缓解的脆弱性，并且5-HT2CR音调的归一化可能有助于抑制由冲动性和提示反应性促进的继电器。我们假设5-HT2CR的一个小分子阳性变构调节剂（PAM）增强了对内源性5-HT和/或外源性5-HT2CR直角配体的反应，是恢复5-HT2CR函数的新型策略。目前的赠款是基于我们基于唯一报道的选择性的5-HT2CR PAM PAM PAM PAM PAM-69176E在理性设计，合成和药物评估方面的进展而建立的。我们合成了新的小分子（例如CYD-1-79，CYD-3-30，CYD-6-16-2），该分子将初始曲线暴露为5-HT2CR PAM（活细胞中的功能信号，放射性结合测定法中的功能信号）以及合理的口服和脑生物可利用性。体内行为研究表明，CYD-1-79以不影响一般运动活动的剂量增强了选择性5-HT2CR激动剂在药物歧视分析中的影响，并抑制了大鼠的冲动性和提示反应性，表明效率效率 在主要动物模型中，与可卡因使用障碍有关。我们的目标是优化具有有利的药物代谢和药代动力学（DMPK）概况的5-HT2CR PAM，并分析概念验证行为模型中的某些分子，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）在体外定义了5-HT2CR PAM的选择性和特异性以及DMPK曲线； （3）确定体内DMPK和在冲动性和提示反应性的啮齿动物模型中优化的5-HT2CR PAM的有效性。这个创新的，潜在的高影响小分子开发项目将阐明有关5-HT2CR变构调制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雷神药物的新概念和方向。