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 alpha 4 beta 2 nAChR ligands, was replaced with nitrogen. The resulting four diastereoisomeric pairs of pyrrolidinyl-pyridodioxanes were studied for the nicotinic affinity and activity at alpha 4 beta 2, alpha 3 beta 4 and alpha 7 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 alpha 4 beta 2 affinity of [(S,R)-6], but also greatly improved in selectivity over the alpha 3 beta 4 and alpha 7 subtypes and, most importantly, exhibited a highly selective alpha 4 beta 2 partial agonism. The finding that [(S,R)-6] is, instead, an unselective alpha 4 beta 2 antagonist indicates that the benzodioxane substructure confers affinity for the alpha 4 beta 2 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. (C) 2016 Elsevier Masson SAS. All rights reserved.