Modifications at C(5) of 2‑(2-Pyrrolidinyl)-Substituted 1,4-Benzodioxane Elicit Potent α4β2 Nicotinic Acetylcholine Receptor Partial Agonism with High Selectivity over the α3β4 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 α4β2 and α3β4
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 α4β2/α3β4
selectivity to the α4β2 partial agonism. Docking into
the two receptor structures recently determined by cryo-electron microscopy
and site-directed mutagenesis at the minus β2 side converge
in indicating that the limited accommodation capacity of the β2
pocket, compared to that of the β4 pocket, makes substitution
at C(5) rather than at more projecting C(7) position determinant for
this pursued subtype selectivity.