Development and characterization of heterocyclized dipeptide derivatives as inhibitors for heterotrimeric G proteins

异三聚体G蛋白作为分子开关，通过G蛋白偶联受体将细胞外信号转导为细胞内信号级联。该项目的这一部分旨在开发5,6,7,8-四氢咪唑[1,2-a]吡嗪作为Ga蛋白亚家族选择探针的重点文库。这种探针将非常需要了解G蛋白信号在生理和病理生理条件下的详细贡献。工具化合物的设计基于两个低分子量、细胞渗透性BIM分子的结构。这些被认为是杂环二肽衍生物，可通过组合化学进行多种结构修饰。在逐步优化的过程中，化合物的选择性和适宜性可以提高到什么程度，需要进一步研究。新化合物将提供给该联盟的合作者进行生化和药理评价和利用。

Heterotrimeric G proteins act as molecular switches and transduce extracellular signals via G protein-coupled receptors into intracellular signal cascades. This part of the project is aimed at developing focused libraries of 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazines as Ga protein subfamily selective probes. Such probes would be highly desired to understand the detailed contribution of G protein signaling under physiological and pathophysiological conditions. The design of the tool compounds is based on the structures of two low-molecular weight, cell-permeable BIM molecules. These are considered as heterocyclized dipeptide derivatives, accessible for manifold structural modifications via combinatorial chemistry. It should be investigated to what extent the selectivity and suitability of the compounds can be improved in the course of a stepwise optimization. The new compounds will be provided to the collaborators of the consortium for biochemical and pharmacological evaluation and utilization.