Design and Synthesis of a Novel Series of Phosphonate-functionalized 1,2,3-triazoles as Positive Allosteric Modulators of α7 Nicotinic Acetylcholine Receptors

NIELSEN, B.E; STABILE, S.A; BOUZAT, C.; VITALE, C.A

San Luis

Congreso; XLVIII Reunión Anual de la Sociedad Argentina de Biofísica; 2019

SAB

α7 nicotinic acetylcholine receptors are pentameric ligand gated ion channels widelydistributed throughout the central nervous system, mainly in hippocampus and cortex.As α7 plays an important role in memory and cognition, the enhancement of its activityby positive allosteric modulators (PAMs) is a promising therapeutic strategy for cognitivedeficits and neurodegenerative disorders. We designed and synthesized a novel series ofphosphonate-functionalized 1,4-disubstituted 1,2,3-triazoles using supported coopernanoparticles as cycloaddition reaction catalyst, and evaluated their activity on α7receptors by electrophysiological techniques. We identified several compounds thatdisplayed a type I PAM activity, which was evidenced by the increase of the peak currentelicited by acetylcholine with minimal effects on desensitization. At the single-channellevel, the active compounds did not affect channel amplitude and increased the durationof openings and activation episodes as observed for type I PAMs. We applied structureactivity relationship (SAR) strategies on the most effective compounds to obtainderivatives with higher effect by modifying the chain length, inverting triazol geometryand varying the aromatic nucleus. Our findings revealed that the phosphonatefunctionalized1,4-disubstituted 1,2,3-triazole is a key pharmacophore for thedevelopment of potential therapeutic agents.