5-HT2 Receptor Allosterism in Cocaine Use Disorder

可卡因使用障碍中的 5-HT2 受体变构

• 批准号: 10445173
• 负责人: Kathryn A. Cunningham
• 金额: $ 53.75万
• 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 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445173
• 关键词: Address; Affect; Agonist; Allosteric Site; Behavioral; Behavioral Model; Binding; Biological Assay; Brain Diseases; Categories; Cellular Assay; Chemicals; Cocaine; Cocaine use disorder; Cognitive; Communities; Cues; Development; Dimensions; Docking; Drug Kinetics; Drug Targeting; Drug usage; Elements; FDA approved; Family; Funding; Generations; Goals; In Vitro; Individual; Knowledge; Lifestyle-related condition; Ligands; Lighting; Link; Medical; Modeling; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pre-Clinical Model; Property; Public Health; Rattus; Recovery; Relapse; Risk; Rodent; Science; Serotonin; Serotonin Receptor 5-HT2C; Signal Transduction; Site; Societies; Specificity; Stress; System; Therapeutic; Treatment Efficacy; Withdrawal; antagonist; behavioral phenotyping; clinical diagnosis; cocaine exposure; craving; drug discovery; drug metabolism; drug relapse; improved; in silico; in vivo; in vivo evaluation; innovation; interdisciplinary approach; male; member; molecular modeling; negative affect; neuropsychiatric disorder; next generation; novel; novel therapeutic intervention; positive allosteric modulator; programs; psychologic; public health emergency; rational design; receptor; small molecule; social

Cocaine use disorder (CUD) is diagnosed by clinical indicators (e.g., risky drug use, social/interpersonal difficulties linked to use, withdrawal/tolerance, failed efforts to control use, etc.), while craving (a strong desire or urge to take a drug) and relapse which can be linked to elevated stress and negative affect and compounded by exposure to cocaine and cocaine-associated environmental cues. Our team and others established that dampened signaling through the serotonin (5-HT) 5-HT2C receptor (5-HT2CR), a member of the 5-HT2R family, is a key element of the mechanisms of action underlying cognitive and behavioral vulnerability to CUD and relapse. We pioneered the development of positive allosteric modulators (PAMs) for the 5-HT2CR and discovered our first generation of 5-HT2CR PAMs to bind to an identified, spatially distinct allosteric site to selectively potentiate 5-HT2CR, but not 5-HT2AR or 5-HT2BR, signaling in vitro without intrinsic activity at the three these receptors. As a proof-of-concept, two of our 5-HT2CR PAMs (CYD-1-79, CTW0415) potentiated in vivo effects of a full 5-HT2CR agonist in male rats, an effect which was blocked by a selective 5-HT2CR antagonist, verifying reliance on 5-HT2CR function. CYD-1-79 also suppressed cocaine-seeking in a relapse-like behavioral model in male rats. Our objectives are to optimize 5-HT2CR PAMs with favorable drug-like properties and analyze select molecules in proof-of-concept in vivo assays and models of CUD. To accomplish our goals, we will pursue three aims to discover next generation 5-HT2CR PAMs for illumination of 5-HT2CR allosterism, optimize 5-HT2CR PAMs with favorable drug metabolism and pharmacokinetics profiles which will be assessed for efficacy in rodent preclinical models of CUD. There is a gap in our ability to maximize therapeutic strategies to reduce the psychological and medical impact of CUD in patients. We address this gap in treatment efficacy by presenting the novel concept that 5-HT2CR may prove useful in treating CUD. Importantly, the advances in novel molecule discovery and expansion of knowledge of allosteric modulation of the 5-HT2CR systems could have a profound impact in improving the course and treatment of an even broader category of neuropsychiatric disorders.

可卡因使用障碍(CUD)的诊断依据是临床指标(例如，危险的药物使用、与使用有关的社交/人际困难、戒毒/耐受、未能控制使用等)，同时渴望(强烈的吸毒欲望或冲动)和复发，这可能与增加的压力和负面影响有关，并因暴露于可卡因和与可卡因有关的环境线索而加剧。我们的团队和其他人证实，通过5-羟色胺(5-HT)5-HT2C受体(5-HT2CR)抑制信号的是5-HT2R家族的成员 认知和行为易患CUD和复发的行动机制的关键要素。我们率先开发了5-HT2CR的正变构调节剂(PAM)，并发现我们的第一代5-HT2CR PAM可以结合到一个确定的、空间上不同的变构位点，选择性地增强5-HT2CR，而不是5-HT2AR或5-HT2BR，在体外对这三种受体没有内在活性。作为概念验证，我们的两个5-HT2CR PAM(CyD-1-79，CTW0415)在雄性大鼠体内增强了完整的5-HT2CR激动剂的作用，这种作用被选择性的5-HT2CR拮抗剂阻断，证实了对5-HT2CR功能的依赖。Cyd-1-79还抑制了雄性大鼠在类似复发的行为模型中寻找可卡因的行为。我们的目标是优化具有良好类药物性能的5-HT2CR PAM，并在体内概念验证试验和CUD模型中分析选定的分子。为了实现我们的目标，我们将追求三个目标：发现新一代5-HT2CR PAM用于照明5-HT2CR变构，优化具有良好药物代谢和药代动力学特征的5-HT2CR PAM，并将其用于CUD啮齿动物临床前模型的疗效评估。我们在最大化治疗策略以减少CUD对患者的心理和医学影响的能力方面存在差距。我们通过提出5-HT2CR可能被证明在治疗CUD中有用的新概念来解决这一治疗效果上的差距。重要的是，新分子发现的进展和5-HT2CR系统变构调节知识的扩展可能会对改善更广泛类别的神经精神疾病的病程和治疗产生深远影响。