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

异源三聚体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换为细胞内信号级联。该项目的这一部分旨在开发作为Ga蛋白亚家族选择性探针的5，6，7，8-四氢咪唑并[1，2-a]吡嗪的聚焦文库。这些探针将是非常需要的，以了解详细的贡献G蛋白信号在生理和病理生理条件下。工具化合物的设计基于两种低分子量、细胞可渗透的BIM分子的结构。这些被认为是杂环化的二肽衍生物，可通过组合化学进行多种结构修饰。应研究在逐步优化过程中化合物的选择性和适用性可以提高到何种程度。新化合物将提供给该联盟的合作者进行生物化学和药理学评价和利用。

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.