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.

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.我们的团队和其他团队确定通过5- ht2c受体（5-HT2C）受到5-HT2R家族的成员的抑制信号（5-HT）。 作用机制的关键要素是认知和行为脆弱性和复发的行为脆弱性。我们开发了5-HT2CR的阳性变构调节剂（PAM）的开发，并发现了我们的第一代5-HT2CR PAM与确定的，空间上不同的变构位点结合，以选择性地增强5-HT2CR，但没有5-HT2AR或5-HT2BR，但没有5-HT2BR，在没有三个受体的情况下发出了固有活性的信号。作为概念验证，我们的5-HT2CR PAM（CYD-1-79，CTW0415）中有两个在雄性大鼠中增强了体内效应的体内效应，这种作用被选择性的5-HT2CR拮抗剂阻断，从而证明了对5-HT2CR功能的依赖性。 CYD-1-79还抑制了雄性大鼠复发样行为模型中的可卡因寻求可卡因。我们的目标是优化具有良好药物样性能的5-HT2CR PAM，并分析体内概念概念和CUD模型的概念概念中的精选分子。为了实现我们的目标，我们将追求三个目标，以发现下一代5-HT2CR PAM来照明5-HT2CR变构主义，优化具有有利的药物代谢和药代动力学概况的5-HT2CR PAM，这些配置文件将在CUD的啮齿动物临时模型中评估。我们最大程度地提高治疗策略来减少患者心理和医学影响的能力存在差距。我们通过提出5-HT2CR可能对治疗CUD有用的新颖概念来解决治疗功效的差距。重要的是，新的分子发现和扩展5-HT2CR系统变构调节知识的进步可能会对改善更广泛的神经精神疾病的过程和治疗产生深远的影响。