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）是通过临床指标诊断的（例如，有风险的药物使用，与使用有关的社会/人际困难，戒断/耐受性，控制使用的努力失败等），而渴望（强烈的欲望或吸毒的冲动）和复发可能与压力升高和负面影响有关，并与暴露于可卡因和可卡因相关的环境线索有关。我们的团队和其他研究人员发现，5-羟色胺（5-HT） 5-HT2C受体（5-HT2CR）的信号传导受到抑制，这是5-HT2R家族的一员