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Funct character of GABA_B receptor modulators, drug metabolism, pharmacokinetics

GABA_B受体调节剂的功能特点、药物代谢、药代动力学

基本信息

批准号：
8378111
负责人：
Patrick Robert Griffin
金额：
$ 59.53万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
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/8378111
关键词：
Agonist Animal Model Automobile Driving Bioavailable Biological Assay Biological Availability Biosensor Brain Butyric Acids Calcium Cell Line Cells Cessation of life Chemicals Clinical Computer Simulation Computer software Coupled Cyclic AMP Data Development Dose Drug Addiction Drug Interactions Drug Kinetics Drug or chemical Tissue Distribution Drug toxicity Dyes Evaluation Exposure to GABA Agonists GABA-B Receptor Goals Hepatic Hour Housing Image In Vitro Laboratories Lead Liver Measures Methodology Methods Monitor Neurons Nicotine Dependence Oral Penetration Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phosphorylation Property Protocols documentation Rattus Reader Recombinants Research Research Project Grants Series Solubility Testing Therapeutic Intervention Time Tissues Tobacco smoking Triage base cheminformatics computational chemistry computerized tools counterscreen cyclic-nucleotide gated ion channels drug candidate drug metabolism feeding gamma-Aminobutyric Acid in vitro Assay in vivo in vivo Model novel pharmacokinetic model professor programs receptor residence small molecule tool

项目摘要

In vitro functional characterization of GABA_B receptor modulators: The emphasis of this research project is on developing novel cell-based assays suitable to determine potency of GABA_B receptor modulators, counterscreens to assess selectivity of high priority potent modulators, functional assays to elucidate in vitro pharmacology of compounds, in vitro and in vivo drug metabolism screens, and development of cheminformatic approaches for rapid hit expansion and evaluation of chemical space. GABA_B receptor modulators that are synthesized in the laboratory of Professor MG Finn (PI of TSRI La Jolla research project) will be characterized in the aforementioned assays. Compounds with appropriate in vitro potency and pharmacology will be tested for solubility, liver microsomal stability, and in vivo pharmacokinetic properties. Compounds with acceptable in vitro profiles and with adequate in vivo PK properties will be evaluated using in vivo models in Professor Athina Markou's laboratory (PI). Iterative chemical optimization will be employed and supplemented with in silico hit expansion approaches resulting in potent and selective GABA_B modulators.

GABA_B受体调节剂的体外功能表征：本研究项目的重点是开发新的基于细胞的方法，以确定GABA_B受体调节剂的效力，反筛选，以评估高优先级的有效调节剂的选择性，功能分析，以阐明化合物的体外药理学，在体外和体内药物代谢筛选，以及发展化学信息学方法，用于快速命中扩展和评估化学空间。在MG Finn教授（TSRI拉霍亚研究项目的PI）的实验室中合成的GABA_B受体调节剂将在上述测定中表征。将检测具有适当体外效价和药理学的化合物的溶解度、肝微粒体稳定性和体内药代动力学特性。将在Athina Markou教授的实验室（PI）使用体内模型评价具有可接受的体外特征和适当体内PK特性的化合物。将采用迭代化学优化，并补充以计算机命中扩增方法，从而产生有效的和选择性的GABA_B调节剂。