Design and synthesis of a novel series of phosphonate-functionalized 1,2,3-triazoles as positive allosteric modulators of α7 nicotinic acetylcholine receptors

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

San Luis

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

Sociedad Argentina de Biofísica (SAB)

α7 nicotinic acetylcholine receptors are pentameric ligand gated ion channels widely distributed throughout the central nervous system, mainly in hippocampus and cortex. As α7 plays an important role in memory and cognition, the enhancement of its activity by positive allosteric modulators (PAMs) is a promising therapeutic strategy for cognitive deficits and neurodegenerative disorders. We designed and synthesized a novel series of phosphonate-functionalized 1,4-disubstituted 1,2,3-triazoles using supported copper nanoparticles as cycloaddition reaction catalyst and evaluated their activity on α7 receptors by electrophysiological techniques. We identified several compounds that displayed a type I PAM activity, which was evidenced by the increase of the peak current elicited by acetylcholine with minimal effects on desensitization. At the single-channel level, the active compounds did not affect channel amplitude and increased the duration of openings and activation episodes as observed for type I PAMs. We applied structure activity relationship (SAR) strategies on the most effective compounds to obtain derivatives with higher effect by modifying the chain length, inverting triazole geometry and varying the aromatic nucleus. Our findings revealed that the phosphonate-functionalized 1,4-disubstituted 1,2,3-triazole is a key pharmacophore for the development of potential therapeutic agents.