Evidence of a dual mechanism of action underlying the anti-proliferative and cytotoxic effects of ammonium-alkyloxy-stilbene-based α7- and α9-nicotinic ligands on glioblastoma cells

From 2-Triethylammonium Ethyl Ether of 4-Stilbenol (MG624) to Selective Small-Molecule Antagonists of Human α9α10 Nicotinic Receptor by Modifications at the Ammonium Ethyl Residue

“…Upon conversion by Finkelstein reaction to the iodo-derivative 29, treatment with a selected variety of secondary amines provided the tertiary amines 30-34 and 37-40, which were quaternarized by treatment with either methyl or ethyl iodide or benzyl bromide to the corresponding quaternary ammonium iodide or bromide salts (4-10, 13-16). Likewise, the reaction between the 29); (c) diethylamine, THF, reflux, overnight, 94% (30), dimethylamine 2M in THF, THF, 40°C, overnight, 92% (31), Nmethylcyclohexylamine, toluene, 60 °C, 5h, 71% (32), dicyclohexylamine, toluene, reflux, overnight, 74% (33), dibenzylamine, toluene, reflux, overnight, 75% (34), 1-adamantylamine, toluene, reflux, 6h, 72% (35), quinuclidine, toluene, reflux, 1h, 95% (12), azetidine, DMF, rt, 3h, 95% (37), pyrrolidine, THF, reflux, overnight, 95% (38), pyperidine, toluene, reflux, overnight, 91% (39), morpholine, toluene, reflux, overnight, 84% (40); pyridine, 50 °C, 3h, 92% (17); (d) MeI, DCM, 35 °C, overnight, 94% (4), THF, rt; overnight, 96% (6), DCM, reflux, overnight, 74% (7), 62% (8), THF, reflux, overnight, 65% (10), toluene, reflux, overnight, 73% (11), DCM, reflux, 3h, 65% (13), DCM, reflux, overnight, 95% (14), 94% (15), 92% (16); (e) BnBr, THF, reflux, overnight, 72% (9); (f) EtI, THF, reflux, overnight, 86% (5); (g) pic-BH 3 , CH 2 O aq. 37%, MeOH/DCM, AcOH, rt, overnight, 80% (36).…”

“…For example, α7-and α9*-nAChR are overexpressed in multiple tumor types, where activation of either promotes tumor cell growth, and inhibition has antiproliferative effects. [9][10][11] For instance, analogues of the 2-triethylammoniumethyl ether of 4stilbenol (1, MG624) with a lengthened alkylene linker between charged nitrogen and ethereal oxygen…”

α9-Containing Nicotinic Receptors in Cancer

“…Hybridization of MG624 and a non-nicotinic, resveratrolderived pro-oxidant mitocan (Bavo et al, 2018) has led to the development of two novel compounds (StN-4 and StN-8) that are more potent than MG624 in reducing the viability of GBM cells, but less potent in reducing the viability of mouse astrocytes (Bavo et al, 2018). Knocking down the α9 subunit in U87MG cells decreases the potency of the effects of both compounds on cell viability, thus clearly indicating that α9-containing nAChRs are involved in sustaining GBM cell growth and survival (Pucci et al, 2022).…”

Neurotransmitters: Potential Targets in Glioblastoma

“…Since many experiments and public databases (such as accession number GSE16805) have proved that the expression of α9 nAChRs is higher in GBM [ 27 , 32 , 34 ] (no expression in normal mammalian brain [ 168 , 169 , 170 ], α9 nAChRs may be a powerful promising target. Atracurium Besylate (nAChR antagonist) [ 32 ], MG624 (α7 and α9 nAChR antagonist) [ 137 ] and StN-4/StN-8 (α7 and α9/10 nAChR antagonist) [ 138 ] have shown significant inhibitory effect on the viability of GBM/GSC cell lines. However, it has been reported that some of their anti-tumoral effects are nAChR-independent, which increases the difficulty of elaborating their mechanisms in GBM and needs additional investigations [ 35 , 138 ].…”

“…Atracurium Besylate (nAChR antagonist) [ 32 ], MG624 (α7 and α9 nAChR antagonist) [ 137 ] and StN-4/StN-8 (α7 and α9/10 nAChR antagonist) [ 138 ] have shown significant inhibitory effect on the viability of GBM/GSC cell lines. However, it has been reported that some of their anti-tumoral effects are nAChR-independent, which increases the difficulty of elaborating their mechanisms in GBM and needs additional investigations [ 35 , 138 ]. Strikingly, targeted drugs for AChRs combined with chemotherapeutic agents represent a new prospective treatment for GBM.…”