Di-aryl guanidinium derivatives: Towards improved ?2-Adrenergic affinity and antagonist activity

Compounds with excellent receptor engagement displaying ?2-AR antagonist activity are useful not only for therapeutic purposes (e.g. antidepressants), but also to help in the crystallization of this particular GPCR. Therefore, based on our broad experience topic, we have prepared eighteen di-aryl (phenyl and/or pyridin-2-yl) mono- or di-substituted guanidines and 2-aminoimidazolines. The vitro binding affinity experiments human brain tissue showed advantage a 2-aminoimidazolinium cation, di-arylmethylene core, conformationally locked pyridin-2-yl-guanidine guanidinium achieve good engagement. After different [35S]GTP?S prefrontal cortex tissue, it was possible identify that compounds 7a, 7b 7c were partial agonist, whereas 8h potent antagonist. Docking MD studies model ?2A-AR two crystal structures suggest antagonism is achieved by carrying guanidine which substituent occupy pocket adjacent TM5 without engaging S2005.42 S2045.46, mono-substituted cationic group, favorably interacts E942.65.