Di-aryl guanidinium derivatives: Towards improved α2-Adrenergic affinity and antagonist activity.

Compounds with excellent receptor engagement displaying α-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 α-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 α-AR engagement. After different in vitro [S]GTPγS binding experiments in human prefrontal cortex tissue, it was possible to identify that compounds 7a, 7b and 7c were α-AR partial agonist, whereas 8h was a potent α-AR antagonist. Docking and MD studies with a model of α-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 or S204, and a mono-substituted cationic group, which favorably interacts with E94.