Synthesis of a cytisine/epibatidine hybrid: a radical approach

With the aim of developing a new ligand of neuronal nicotinic receptors (nAChRs), ionic, and radical routes to the synthesis of a cytisine/epibatidine hybrid were studied. The key step of the convergent synthesis was an unprecedented intramolecular coupling between a primary radical and a pyridine heterocycle. The target compound ‘6,11-diaza’ was formed with its ‘4,11-diaza’ regioisomer (‘6,11″/’4,11″: 70/30). Both compounds exhibited a nanomolar affinity at the α4β2 nAChR subtype, slightly better for the unexpected regioisomer [Ki (nM) target compound and its regioisomer: 3.5 and 0.5 nM, respectively].