Novel ligands for neuronal nicotinic receptor subtypes: synthetic, pharmacological and molecular docking studies

Neuronal nicotinic acetylcholine receptors (nAChRs) are pentameric proteins made up of homomeric or heteromeric combinations of α and α/β subunits, whose differential association confers specific structural and functional properties to the resulting subtypes. The α4β2 and the α7 nAChRs are by far the most expressed in the central nervous system (CNS), whereas the α3β4 subtype is predominant in the sensory and autonomic ganglia and in a subpopulation of neurons in the medial habenula (MHN) and interpeduncular nucleus (IPN) in the CNS [1]. Recently, behavioral and functional studies have further indicated the crucial role of nAChRs in nicotine reward, addiction and expression of withdrawal. The α4 and β2 subunits appear to be crucial for nicotine dependence and the α3β4 nAChR subtype seems to be implicated in addiction to nicotine and other drugs of abuse [2]. As an extension of our research in this field [3], we aimed at deepening the investigation on the involvement of nAChR subtypes in each of the aspects of tobacco addiction. To such an end, we designed and synthesized the set of novel compounds 4-9, which may be related to Nicotine 1, Epibatidine 2 and Anabaseine 3. In the new derivatives, the pyridine ring featuring the parent ligands was replaced by a 3-hydroxybenzene or a 3-hydroxymethylbenzene moiety. The synthetic approach to the target compounds, the data of their pharmacological screening as well as the results of molecular modeling investigations will be presented and discussed.