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

NIELSEN, BEATRIZ ELIZABETH; STABILE, SANTIAGO; VITALE, CRISTIAN; BOUZAT, CECILIA

ACS Chemical Neuroscience

American Chemical Society

Lugar: Whasington, DC.; Año: 2020

1948-7193

α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel widelydistributed in the central nervous system, mainly in hippocampus and cortex. Theenhancement of its activity by positive allosteric modulators (PAMs) is a promisingtherapeutic strategy for cognitive deficits and neurodegenerative disorders. With the aimof developing novel scaffolds with PAM activity, we designed and synthesized a seriesof phosphonate-functionalized 1,4-disubstituted 1,2,3-triazoles using supported coppernanoparticles as cycloaddition reaction catalyst, and evaluated their activity on α7receptors by single-channel and whole-cell recordings. We identified several triazolederivatives that displayed PAM activity, the compound functionalized with the methylphosphonate group being the most efficacious one. At the macroscopic level, α7potentiation was evidenced as an increase of the maximal currents elicited byacetylcholine with minimal effects on desensitization, recapitulating the actions of type IPAMs. At the single-channel level, the active compounds did not affect channelamplitude, but significantly increased the duration of channel openings and activationepisodes. By using chimeric and mutant α7 receptors, we demonstrated that the new α7PAMs share transmembrane structural determinants of potentiation with otherchemically non-related PAMs. To gain further insight into the chemical basis ofpotentiation, we applied structure-activity relationship strategies involving modification ofthe chain length, inversion of substituent positions in the triazole ring and changes in thearomatic nucleus. Our findings revealed that the phosphonate-functionalized 1,4-disubstituted 1,2,3-triazole is a novel pharmacophore for the development of therapeuticagents for neurological and neurodegenerative disorders associated to cholinergicdysfunction.