NOVEL PROBES FOR THE STUDY OF 5-HT2R NEUROBIOLOGY

用于研究 5-HT2R 神经生物学的新型探针

• 批准号: 7904921
• 负责人: SCOTT R GILBERTSON
• 金额: $ 15.41万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7904921
• 关键词: Abstinence; Agonist; Animals; Behavioral; Benign; Binding; Biological; Biology; Cell membrane; Cell model; Cells; Characteristics; Chemistry; Clinical; Clinical Research; Cocaine; Cocaine Dependence; Data; Development; Dimerization; Equilibrium; Exhibits; Genetic Polymorphism; Genotype; Goals; Heterodimerization; Homodimerization; Human; Individual; Investigation; Knowledge; Length; Letters; Life; Ligands; Link; Location; Methodology; Modeling; Molecular; Molecular Biology; Neurobiology; Organism; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Population; Process; Psychopharmacology; Psychostimulant dependence; Relapse; Research; Rodent; Role; Series; Serotonin; System; Testing; Therapeutic; Validation; Work; abstracting; addiction; analog; base; craving; design; dimer; high risk; innovation; insight; interest; knowledge base; molecular shape; monomer; novel; pre-clinical; receptor; serotonin receptor; structural biology; therapeutic development; therapeutic target; tool; treatment strategy

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.

关于成瘾的多巴胺能神经生物学贡献的新知识可以用于 设计新的药物疗法的基础上，肾上腺素能机制。临床前研究结果强烈表明 5-HT 2AR拮抗剂、5-HT 2cR激动剂或具有这些作用的组合的配体可能是 有效的方法，以减少渴望和提高戒瘾。项目3的目标 5-羟色胺和兴奋剂成瘾转化中心（TCSSA）将利用药物化学 产生两个5-HT 2AR拮抗剂分子或两个5-HT 2cR 具有增加对这些受体的选择性的前景的激动剂分子，以及一系列二价的 在一些实施方案中，本发明涉及含有选择性5-HTaAR拮抗剂分子和5-HT 2CR激动剂分子的异二聚体。的 二聚体将基于高选择性5-HT 2CR拮抗剂M100907和5-HT 2CR激动剂WAY 470。 鉴于对5-HT配体如何与它们各自的受体相互作用的有限了解， 将检查每个分子。这些类似物将基于系链连接到神经元的点而不同。 分子。在合成在这些位置连接的二聚体之前， 将对拥有系绳模型的人员进行综合和评估，以确定 依恋是良性的项目3将与核心B密切合作，筛选这些新分子的功能 野生型5-HT^R和5-HT 2CR以及具有遗传多态性的5-HT^R和5-HT 2CR的活性 可卡因依赖人群的特点（项目1）。这项发现研究将创造重要的 对多巴胺能系统及其在成瘾生物学中作用的机制性理解（与核心B，项目 2)并将这些与临床见解结合在一起，促进人类的“概念验证”（项目1）。 项目3代表了一个高风险/探索性的项目，也是人类和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， 设计新分子，推动生物学和化学界面的创新， 生物医学和临床研究。利用在这一发展时期获得的知识，我们将建立 基于我们对5-HT 2AR和5-HT 2CR的分子、细胞和结构生物学的新理解， 以及生命系统中二聚化的新兴生物学，以提出更多的发现策略。 拉夫摘要。目前还没有有效的、可获得的治疗兴奋剂成瘾的药物。 available.我们将设计和创造新的药物，以提高禁欲和减少复发的承诺 对可卡因的依赖