Di-Aryl Guanidinium Derivatives: Towards Improved Alpha 2-Adrenergic Affinity And Antagonist Activity

Compounds with excellent receptor engagement displaying alpha(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 in the topic, we have prepared eighteen di-aryl (phenyl and/or pyridin-2-yl) mono- or di-substituted guanidines and 2-aminoimidazolines. The in vitro alpha(2)-AR binding affinity experiments in human brain tissue showed the advantage of a 2-aminoimidazolinium cation, a di-arylmethylene core, a conformationally locked pyridin-2-yl-guanidine and a di-substituted guanidinium to achieve good alpha(2)-AR engagement. After different in vitro [S-35]GTP gamma S binding experiments in human prefrontal cortex tissue, it was possible to identify that compounds 7a, 7b and 7c were alpha(2)-AR partial agonist, whereas 8h was a potent alpha(2)-AR antagonist. Docking and MD studies with a model of alpha(2A)-AR and two crystal structures suggest that antagonism is achieved by compounds carrying a di-substituted guanidine which substituent occupy a pocket adjacent to TM5 without engaging S200(5.42) or S204(5.46), and a mono-substituted cationic group, which favorably interacts with E94(2.65). (c) 2020 Elsevier Masson SAS. All rights reserved.