Synthesis and binding studies of epibatidine analogues as ligands for the nicotinic acetylcholine receptors

Neuronal nicotinic acetylcholine receptors (nAChRs) are transmembrane ligand-gated ion channels. Recent research demonstrated that selective nAChR ligands may have therapeutic potential in a number of CNS diseases and disorders. The alkaloid epibatidine is a highly potent non-opioid analgesic and nAChR agonist, but too toxic to be a useful ligand. To develop ligands selective for distinct nAChR subtypes and with reduced toxicity, a series of epibatidine and homoepibatidine analogues were synthesized. (±)-8-Methyl-3-(pyridin-3-yl)-8-azabicyclo[3,2,1]oct-2-ene, showed high affinity towards α4β2 (Ki = 2 nM), subtype selectivity (α4β2/α7 affinity ratio > 100) and relatively low toxicity in mice and can be labeled with 11C and 18F as positron emission tomography (PET) tracers for imaging of nAChRs.

A series of epibatidine analogues were synthesized. (±)-8-Methyl-3-(pyridin-3-yl)-8-azabicyclo[3,2,1]oct-2-ene showed high affinity towards α4β2 nAChRs (Ki = 2 nM) and subtype selectivity (α4β2/α7 affinity ratio > 100).Figure optionsDownload as PowerPoint slide