Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a super-family of Cys-loop ligand-gated ion chan-nels that respond to endogenous acetylcholine (ACh) or other cholinergic ligands. These receptors are also the targets of drugs such as nicotine (the main addictive agent delivered by cigarette smoke) and are involved in a variety of physiological and pathophysiological processes. Numerous studies have shown that the expression and/or function of nAChRs is com-promised in many neurological and psychiatric diseases.Furthermore, recent studies have shown that neuronal nAChRs are found in a large number of non-neuronal cell types in-cluding endothelial cells, glia, immune cells, lung epithelia and cancer cells where they regulate cell differentiation, prolifera-tion and inflammatory responses.The aim of this review is to describe the most recent findings concerning the structure and function of native nAChRs inside and outside the nervous system.

This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc.

Adenocarcinoma and glioblastoma cell lines express α7and α9α10-containing nicotinic acetylcholine receptors (nAChRs), whose activation promotes tumor cell growth. On these cells, the triethylammoniumethyl ether of 4-stilbenol MG624, a known selective antagonist of α7 and α9α10 nAChRs, has antiproliferative activity. The structural analogy of MG624 with the mitocan RDM-4′BTPI, triphenylphosphoniumbutyl ether of pterostilbene, suggested us that molecular hybridization among their three substructures (stilbenoxy residue, alkylene linker, and terminal onium) and elongation of the alkylene linker might result in novel antitumor agents with higher potency and selectivity. We found that lengthening the ethylene bridge in the triethylammonium derivatives results in more potent and selective toxicity toward adenocarcinoma and glioblastoma cells, which was paralleled by increased α7 and α9α10 nAChR antagonism and improved ability of reducing mitochondrial ATP production. Elongation of the alkylene linker was advantageous also for the triphenylphosphonium derivatives resulting in a generalized enhancement of antitumor activity, associated with increased mitotoxicity.

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