5-HT2 Receptor Allosterism in Cocaine Use Disorder

通过临床指标（例如，危险药物使用、与使用有关的社会/人际关系困难、戒断/耐受、未能控制使用等），而渴望（强烈的欲望或冲动服用药物）和复发，这可能与压力升高和负面影响有关，并因暴露于可卡因和可卡因相关的环境线索而加剧。我们的团队和其他研究人员确定，通过5-羟色胺（5-HT）5-HT 2C受体（5-HT 2CR）（5-HT 2 R家族的一员）的信号传导受到抑制， 一个关键因素的行动机制的基础认知和行为的脆弱性CUD和复发。我们率先开发了5-HT 2CR的正变构调节剂（PAM），并发现了我们的第一代5-HT 2CR PAM结合到已鉴定的、空间上不同的变构位点，以选择性地增强5-HT 2CR而不是5-HT 2AR或5-HT 2BR的体外信号传导，而对这三种受体没有内在活性。作为概念验证，我们的两种5-HT 2CR PAM（CYD-1-79，CTW 0415）在雄性大鼠中增强了完全5-HT 2CR激动剂的体内作用，该作用被选择性5-HT 2CR拮抗剂阻断，验证了对5-HT 2CR功能的依赖性。CYD-1-79还在雄性大鼠的复发样行为模型中抑制可卡因寻求。我们的目标是优化具有良好药物样性质的5-HT 2CR PAM，并在CUD的体内试验和模型中分析概念验证中选择的分子。为了实现我们的目标，我们将追求三个目标：发现下一代5-HT 2CR PAM用于照明5-HT 2CR变构，优化具有良好药物代谢和药代动力学特征的5-HT 2CR PAM，其将在啮齿动物临床前模型中评估CUD的疗效。我们在最大限度地利用治疗策略以减少CUD对患者的心理和医学影响方面存在差距。我们通过提出5-HT 2CR可能被证明在治疗CUD中有用的新概念来解决治疗效果的这一差距。重要的是，新分子发现的进展和5-HT 2CR系统变构调节知识的扩展可能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的影响。

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.