Modifications at C(5) of 2-(2-Pyrrolidinyl)-Substituted 1,4-Benzodioxane Elicit Potent alfa4beta2 Nicotinic Acetylcholine Receptor Partial Agonism with High Selectivity over the a3b4 Subtype

A series of diastereomeric 2-(2-pyrrolidinyl)-1,4-benzodioxanes bearing a small, hydrogen-bonding substituent at the 7-, 6-, or 5-position of benzodioxane have been studied for ?4?2 and ?3?4 nicotinic acetylcholine receptor affinity and activity. Analogous to C(5)H replacement with N and to a much greater extent than decoration at C(7), substitution at benzodioxane C(5) confers very high ?4?2/?3?4 selectivity to the ?4?2 partial agonism. Docking into the two receptor structures recently determined by cryo-electron microscopy and site-directed mutagenesis at the minus ?2 side converge in indicating that the limited accommodation capacity of the ?2 pocket, compared to that of the ?4 pocket, makes substitution at C(5) rather than at more projecting C(7) position determinant for this pursued subtype selectivity.