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

基本信息

批准号：
7390002
负责人：
SCOTT R GILBERTSON
金额：
$ 17.14万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7390002
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 MDL 100907 Methodology Modeling Molecular Molecular Biology Neurobiology Organism Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacotherapy Population Process Psychopharmacology Psychostimulant dependence Relapse Research Risk Rodent Role Series Serotonin System Testing Therapeutic Validation Work abstracting addiction analog base concept craving design desire dimer innovation insight interest knowledge base molecular shape monomer novel pre-clinical receptor serotonin receptor structural biology therapeutic target tool

项目摘要

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.

对成瘾的血清素能神经生物学的贡献的新兴知识可用于根据血清素能机制设计新的药物疗法。临床前发现强烈建议 5-HT2AR拮抗剂，5-HT2CR激动剂或结合这些动作的配体可能是减少渴望和增强成瘾中的禁欲的有用方法。项目3的目标 5-羟色胺和兴奋剂成瘾（TCSSA）的转化中心是利用药物化学创建两个5-HT2AR拮抗剂分子或两个5-HT2CR的一系列二价同二聚体激动剂分子有望提高这些受体的选择性，以及一系列二价含有选择性5-HTAAR拮抗剂分子和5-HT2CR激动剂分子的异二聚体。这二聚体将基于高度选择性的5-HT拮抗剂M100907和5-HT2CR激动剂方式470。鉴于对5-HT配体如何与各自受体相互作用的知识有限，每个分子将被检查。这些类似物将根据系绳与分子。在合成在这些位置链接的二聚体之前，相应的单体控件将合成和评估该系的系绳模型，以确定哪些位置依恋是良性的。项目3将与核心B紧密合作，以筛选这些新分子以进行功能具有遗传多态性的野生型5-HT^r和5-HT2CR以及5-HT^r和5-HT2CR的活性这是可卡因依赖性人群的特征（项目1）。这项发现研究将创造重要对血清素能系统及其在成瘾生物学中的作用的机械理解（核心B，项目 2）并将它们与临床见解一起结合在一起，并促进了人类的“概念验证”（项目1）。项目3代表一个高风险/探索性项目和人与动物之间的转化桥心理药理学，药物化学，分子生物学和药理学，允许理性在生物学和化学的界面以及驱动创新的新分子的设计以及生物医学和临床研究。随着在这个发展时期获得的知识，我们将建立根据我们对5-HT2AR和5-HT2CR的分子，细胞和结构生物学的新理解以及生命系统中二聚体化的新兴生物学提出了其他发现策略。 LAV摘要。目前尚无有效的，可访问的药物治疗兴奋剂成瘾可用的。我们将设计和创建新药，有望增强禁欲并减少复发在可卡因依赖性中。