Funct character of GABA_B receptor modulators, drug metabolism, pharmacokinetics

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适用于确定GABA_B受体调节剂效价的新型细胞检测方法，评估高优先级强效调节剂选择性的反筛选方法，阐明化合物体外药理学的功能检测方法，体外和体内药物代谢筛选方法，以及开发用于快速靶向扩展和化学空间评估的化学信息学方法。在MG Finn教授（TSRI La Jolla研究项目的PI）的实验室合成的GABA_B受体调节剂将在上述分析中进行表征。具有适当的体外效力和药理学的化合物将进行溶解度、肝微粒体稳定性和体内药代动力学特性的测试。具有可接受的体外特征和足够的体内PK特性的化合物将在Athina Markou教授的实验室（PI）使用体内模型进行评估。迭代化学优化将被采用，并辅以硅命中扩展方法，从而产生有效和选择性的GABA_B调节剂。

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.