Octahydropyrrolo[3,4-c]pyrrole: A Diamine Scaffold for Construction of Either α4β2 or α7-Selective Nicotinic Acetylcholine Receptor (nAChR) Ligands. Substitutions that Switch Subtype Selectivity

A series of 5-(pyridine-3-yl)octahydropyrrolo[3,4-c]pyrroles have been prepared that exhibit high affinity to α4β2 and/or α7 nicotinic acetylcholine receptors (nAChRs). Simple substitution patterns have been identified that allow construction of ligands that are highly selective for either nAChR subtype. The effects of substitution on subtype selectivity provide some insight into the differences in the ligand binding domains of the α4β2 and α7 receptors, especially in regions removed from the cation binding pocket.