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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 α 2 -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 α 2 -adrenoceptor in human brain tissue in vitro experiments. Structure-activity relationships have been established for the design and biological evaluation of novel α 2 -adrenoceptor ligands. [ABSTRACT FROM AUTHOR]

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 35S]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 S2005.42 or S2045.46, and a mono-substituted cationic group, which favorably interacts with E942.65. Image 1 • Fifteen di-aryl (phenyl/pyridin-2-yl) guanidinines and 2-aminoimidazolines prepared. • Human brain α 2 -AR binding tests show structural elements rising receptor engagement. • 2-Aminoimidazoline, di-arylmethylene, pyridin-2-yl guanidine ideal for binding. • Human brain α 2 -AR functional tests find 3 partial agonists and 1 potent antagonist. • Modelling suggests antagonism achieved by contact to E94 and filling pocket by TM5. [ABSTRACT FROM AUTHOR]