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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Nicotinic acetylcholine receptors containing α9 subunits (α9*-nAChRs) are potential druggable targets arousing great interest within the nicotinic receptor family with a special focus on a pain treatment alternative to opioids. Non-peptidic small molecules selectively acting as antagonists at this receptor subtype, especially without any effect on the closely related α7-nAChR, still remain an unattained goal, the achievement of which would provide invaluable tools to validate such an approach. Here, through relatively few directed modifications of the cationic head and the ethylene linker, we have converted the 2-triethylammonium ethyl ether of 4-stilbenol (MG624), a well-known antagonist for both α7 and α9* receptors, into a set of selective antagonists of human α9*-nAChR.Among these, the compound with cyclohexyldimetylammonium head (7) stands out for having no agonist or antagonist effect at α7-nAChR along with very low binding affinity at both α7 and α3β4 nicotinic receptor subtypes. Applied alone at high supra-micromolar concentrations, 7 and the other selective α9* antagonists behaved as partial agonists at α9*-nAChRs with a very short duration of the response, most likely due to very rapid block of the open channel, as revealed by the occurrence of rebound current once the application is stopped and the channel is disengaged. The small (nearly null in the case of 7) post-application residual activity of ACh control stimulation seems to be related to the slow recovery of the rebound current.
A series of diastereomeric
2-(2-pyrrolidinyl)-1,4-benzodioxanes
bearing a small, hydrogen-bonding substituent at the 7-, 6-, or 5-position
of benzodioxane have been studied for α4β2 and α3β4
nicotinic acetylcholine receptor affinity and activity. Analogous
to C(5)H replacement with N and to a much greater extent than decoration
at C(7), substitution at benzodioxane C(5) confers very high α4β2/α3β4
selectivity to the α4β2 partial agonism. Docking into
the two receptor structures recently determined by cryo-electron microscopy
and site-directed mutagenesis at the minus β2 side converge
in indicating that the limited accommodation capacity of the β2
pocket, compared to that of the β4 pocket, makes substitution
at C(5) rather than at more projecting C(7) position determinant for
this pursued subtype selectivity.
Neuronal nicotinic acetylcholine receptors containing the α9 or the α9 and α10 subunits are expressed in various extra-neuronal tissues. Moreover, most cancer cells and tissues highly express α9-containing receptors, and a number of studies have shown that they are powerful regulators of responses that stimulate cancer processes such as proliferation, inhibition of apoptosis, and metastasis. It has also emerged that their modulation is a promising target for drug development. The aim of this review is to summarize recent data showing the involvement of these receptors in controlling the downstream signaling cascades involved in the promotion of cancer.
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