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.

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.

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