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Artículo

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 ElizabethIcon ; Stabile, Santiago ArmandoIcon ; Vitale, Cristian AlejandroIcon ; Bouzat, Cecilia BeatrizIcon
Fecha de publicación: 28/07/2020
Editorial: American Chemical Society
Revista: ACS Chemical Neuroscience
ISSN: 1948-7193
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Biofísica

Resumen

The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel widely distributed in the central nervous system, mainly in hippocampus and cortex. The enhancement of its activity by positive allosteric modulators (PAMs) is a promising therapeutic strategy for cognitive deficits and neurodegenerative disorders. With the aim of developing novel scaffolds with PAM activity, we designed and synthesized a 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 single-channel and whole-cell recordings. We identified several triazole derivatives that displayed PAM activity, the compound functionalized with the methyl phosphonate group being the most efficacious one. At the macroscopic level, α7 potentiation was evidenced as an increase of the maximal currents elicited by acetylcholine with minimal effects on desensitization, recapitulating the actions of type I PAMs. At the single-channel level, the active compounds did not affect channel amplitude, but significantly increased the duration of channel openings and activation episodes. By using chimeric and mutant α7 receptors, we demonstrated that the new α7 PAMs share transmembrane structural determinants of potentiation with other chemically non-related PAMs. To gain further insight into the chemical basis of potentiation, we applied structure-activity relationship strategies involving modification of the chain length, inversion of substituent positions in the triazole ring and changes in the aromatic nucleus. Our findings revealed that the phosphonate-functionalized 1,4-disubstituted 1,2,3-triazole is a novel pharmacophore for the development of therapeutic agents for neurological and neurodegenerative disorders associated to cholinergic dysfunction.
Palabras clave: NICOTINIC RECEPTORS , LIGAND-GATED ION CHANNELS , PATCH CLAMP , TRIAZOLE , PHOSPHONATES , CLICK CHEMISTRY
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/143117
DOI: https://doi.org/10.1021/acschemneuro.0c00348
URL: https://pubs.acs.org/doi/10.1021/acschemneuro.0c00348
Colecciones
Articulos(INIBIBB)
Articulos de INST.DE INVEST.BIOQUIMICAS BAHIA BLANCA (I)
Articulos(INQUISUR)
Articulos de INST.DE QUIMICA DEL SUR
Citación
Nielsen, Beatriz Elizabeth; Stabile, Santiago Armando; Vitale, Cristian Alejandro; Bouzat, Cecilia Beatriz; 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; American Chemical Society; ACS Chemical Neuroscience; 11; 17; 28-7-2020; 2688–2704
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