Bolchi_2017_Eur.J.Med.Chem_125_1132

Each of the four aromatic -CH= of (S,R)-2-pyrrolidinyl-1,4-benzodioxane [(S,R)-6] and of its epimer at the dioxane stereocenter (S,S)-6, previously reported as alpha4beta2 nAChR ligands, was replaced with nitrogen. The resulting four diastereoisomeric pairs of pyrrolidinyl-pyridodioxanes were studied for the nicotinic affinity and activity at alpha4beta2, alpha3beta4 and alpha7 nAChR subtypes and compared to their common carbaisostere. It turned out that such isosteric substitutions are highly detrimental, but with the important exception of the S,R stereoisomer of the pyrrolidinyl-pyridodioxane with the pyridine nitrogen adjacent to the dioxane and seven atoms distant from the pyrrolidine nitrogen. Indeed, this stereo/regioisomer not only maintained the alpha4beta2 affinity of [(S,R)-6], but also greatly improved in selectivity over the alpha3beta4 and alpha7 subtypes and, most importantly, exhibited a highly selective alpha4beta2 partial agonism. The finding that [(S,R)-6] is, instead, an unselective alpha4beta2 antagonist indicates that the benzodioxane substructure confers affinity for the alpha4beta2 nAChR binding site, but activation of this receptor subtype needs benzodioxane functionalization under strict steric requirements, such as the previously reported 7-OH substitution or the present isosteric modification.