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.

Graphical abstractA 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 full-size imageDownload as PowerPoint slide