NOVEL PROBES FOR THE STUDY OF 5-HT2R NEUROBIOLOGY

关于成瘾的5-羟色胺能神经生物学贡献的新兴知识可以用来 根据5-羟色胺能机制设计新的药物疗法。临床前研究结果强烈表明 具有这些作用组合的5-HT2AR拮抗剂、5-HT2cR激动剂或配体可能是 有效的方法，以减少渴望和提高戒毒成瘾。项目3的目标是 5-羟色胺和兴奋剂成瘾翻译中心(TCSSA)将利用药物化学 合成两个5-HT2AR拮抗剂分子或两个5-HT2cR二价同二聚体的方法学 激动剂分子，有望增加对这些受体的选择性，以及一系列二价 含有选择性5-HTaAR拮抗剂分子和5-HT2CR激动剂分子的杂二聚体。这个 二聚体将基于高度选择性的5-羟色胺受体拮抗剂M100907和5-HT2CR激动剂Way 470。 鉴于对5-羟色胺配体如何与其各自的受体相互作用的有限了解， 将对每个分子进行检查。这些类比将根据系绳到的连接点而有所不同 分子。在合成连接在这些位置的二聚体之前，相应的单体控制 拥有系绳模型的人将被综合和评估以确定哪些位置 依恋是良性的。项目3将与Core B密切合作，筛选这些新分子的功能 野生型5-羟色胺受体和5-羟色胺受体的活性以及5-羟色胺受体和5-羟色胺受体的活性具有遗传多态性 这是依赖可卡因的人群的特征(项目1)。这项发现研究将创造重要的 对5-羟色胺能系统的机械理解及其在成瘾生物学中的作用(核心B，项目 2)并将这些与临床见解结合起来，促进人类的“概念验证”(项目1)。 项目3是一个高风险/探索性项目，是人与动物之间的翻译桥梁 精神药理学、药物化学、分子生物学和药理学，允许理性的 设计新的分子并推动生物和化学以及 生物医学和临床研究。凭借在这一发展阶段获得的知识，我们将建立 我们对5-HT2AR和5-HT2CR的分子、细胞和结构生物学的新认识 以及生命系统中二聚化的新兴生物学提出了更多的发现策略。 LAV摘要。目前还没有有效的、可获得的治疗兴奋剂成瘾的药物 可用。我们将设计和创造新药，承诺加强戒酒和减少复发 对可卡因的依赖。

Emerging knowledge of the contribution of the serotonergic neurobiology of addiction can be utilized to design new pharmacotherapies based upon serotonergic mechanisms. Preclinical findings strongly suggest that a 5-HT2AR antagonist, a 5-HT2cR agonist or ligands with a combination of these actions might be a useful approach to reduce craving and enhance abstinence in addiction. The goal of Project 3 of the Translational Center for Serotonin and Stimulant Addiction (TCSSA) is to utilize medicinal chemistry methodology to create a series of bivalent homodimers of two 5-HT2AR antagonist molecules or two 5-HT2cR agonist molecules with the promise of increased selectivity for these receptors, as well as a series of bivalent heterodimers containing a selective 5-HTaAR antagonist molecule and a 5-HT2CR agonist molecule. The dimers will be based on the highly selective 5-HT^R antagonist M100907 and 5-HT2CR agonist WAY 470. Given the limited knowledge of how 5-HT ligands interact with their respective receptors, two derivatives of each molecule will be examined. These analogs will differ based upon the point of connection of the tether to the molecule. Prior to synthesizing dimers linked at these locations, the corresponding monomer controls possessing a model for the tether will be synthesized and evaluated to determine which locations of attachment are benign. Project 3 will work closely with Core B to screen these new molecules for functional activity at wild-type 5-HT^R and 5-HT2CR, as well as at 5-HT^R and 5-HT2CR with genetic polymorphisms that characterize the cocaine-dependent population (Project 1). This discovery research will create important mechanistic understanding of the serotonergic system and its role in addiction biology (with Core B, Project 2) and bring these together with clinical insights and facilitate "proof-of-concept" in humans (Project 1). Project 3 represents a high risk/exploratory project and a translational bridge between human and animal psychopharmacology, medicinal chemistry, molecular biology and pharmacology which allows the rational design of new molecules and drives innovation at the interfaces of biology and chemistry as well as biomedical and clinical research. With the knowledge gained during this developmental period, we will build upon our new understanding of the molecular, cellular and structural biology of the 5-HT2AR and 5-HT2CR and the emerging biology of dimerization in living systems to propose additional strategies for discovery. Lav Abstract. No effective, accessible medication for the treatment of stimulant addiction is currently available. We will design and create new drugs with the promise to enhance abstinence and reduce relapse in cocaine dependence.