Ricerc@Sapienza

Each of the four aromatic eCH¼ 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 a4b2 nAChR ligands, was replaced with nitrogen. The resulting four diastereoisomeric pairs of pyrrolidinyl-pyridodioxanes were studied for the nicotinic affinity and activity at a4b2, a3b4 and a7 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 a4b2 affinity of [(S,R)-6], but also greatly improved in selectivity over the a3b4 and a7 subtypes and, most importantly, exhibited a highly selective a4b2 partial agonism. The finding that [(S,R)-6] is, instead, an unselective a4b2 antagonist indicates that the benzodioxane substructure confers
affinity for the a4b2 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.