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Compounds with excellent receptor engagement displaying α 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 α 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 α 2 -AR engagement. After different in vitro [ 35 S]GTPγS binding experiments in human prefrontal cortex tissue, it was possible to identify that compounds 7a, 7b and 7c were α 2 -AR partial agonist, whereas 8h was a potent α 2 -AR antagonist. Docking and MD studies with a model of α 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 ., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

In this paper we report the design, synthesis and pharmacological evaluation of new N-substituted 2-amino-1,4-dihydroquinazolines, 2-amino-1,4-dihydropyridopyrimidines and 2-amino-4,5-dihydro-1,3-benzodiazepines as α2-adrenoceptors ligands. Computational studies show that the proposed substitutions and guanidine-containing ring size will probe an extensive area of the active site. Preparation of these molecules involved novel routes than those previously utilised in our laboratory for the preparation of the acyclic aryl-guanidine counterparts. Compounds 8b and 18c showed the highest affinity and antagonistic activity, within their series, towards the α2-adrenoceptor in human brain tissue in vitro experiments. Structure-activity relationships have been established for the design and biological evaluation of novel α2-adrenoceptor ligands., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)