In silico and in vivo neuropharmacological evaluation of two γ-amino acid isomers derived from 2,3-disubstituted benzofurans, as ligands of GluN1-GluN2A NMDA receptor.

Autor: Coaviche-Yoval A; Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana-Unidad Xochimilco Calzada del Hueso 1100, Col. Villa Quietud, 04960, Coyoacán, CDMX, Mexico.; Instituto de Ciencias Básicas Universidad Veracruzana, Av. Dr. Luis Castelazo Ayala s/n Col. Industrial Animas, Xalapa, 91190, Veracruz, Mexico., Trujillo-Ferrara JG; Departamentos de Bioquímica y Fisiología, Escuela Superior de Medicina-Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n Col. Casco de Santo Tomas, 11340, Miguel Hidalgo, CDMX, Mexico., Soriano-Ursúa MA; Departamentos de Bioquímica y Fisiología, Escuela Superior de Medicina-Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n Col. Casco de Santo Tomas, 11340, Miguel Hidalgo, CDMX, Mexico., Andrade-Jorge E; Departamentos de Bioquímica y Fisiología, Escuela Superior de Medicina-Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n Col. Casco de Santo Tomas, 11340, Miguel Hidalgo, CDMX, Mexico.; Facultad de Estudios Superiores-Iztacala-UNAM, Unidad de Investigación en Biomedicina, Av. De Los Barrios 1, Los Reyes Iztacala, 54090, Tlalnepantla, Edo. De México, Mexico., Sánchez-Labastida LA; Departamentos de Bioquímica y Fisiología, Escuela Superior de Medicina-Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n Col. Casco de Santo Tomas, 11340, Miguel Hidalgo, CDMX, Mexico., Luna H; Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana-Unidad Xochimilco Calzada del Hueso 1100, Col. Villa Quietud, 04960, Coyoacán, CDMX, Mexico. lchm1964@correo.xoc.uam.mx., Tovar-Miranda R; Instituto de Ciencias Básicas Universidad Veracruzana, Av. Dr. Luis Castelazo Ayala s/n Col. Industrial Animas, Xalapa, 91190, Veracruz, Mexico. rtovar@uv.mx.
Jazyk: angličtina
Zdroj: Amino acids [Amino Acids] 2022 Feb; Vol. 54 (2), pp. 215-228. Date of Electronic Publication: 2021 Dec 02.
DOI: 10.1007/s00726-021-03108-2
Abstrakt: The GABAergic and glutamatergic neurotransmission systems are involved in seizures and other disorders of the central nervous system (CNS). Benzofuran derivatives often serve as the core in drugs used to treat such neurological disorders. The aim of this study was to synthesize new γ-amino acids structurally related to GABA and derived from 2,3-disubstituted benzofurans, analyze in silico their potential toxicity, ADME properties, and affinity for the GluN1-GluN2A NMDA receptor, and evaluate their potential activity and neuronal mechanisms in a murine model of pentylenetetrazol (PTZ)- and 4-aminopyridine (4-AP)-induced seizures. The in silico analysis evidenced a low risk of toxicity for the test compounds as well as the probability that they can cross the blood-brain barrier (BBB) to reach their targets in the CNS. According to docking simulations, these compounds bind at the active site of the NMDA glutamate receptor with high affinity. The in vivo assays demonstrated that 4 protects against 4-AP-induced seizure episodes, suggesting negative allosteric modulation (NAMs) at the glutamatergic NMDA receptor. Contrarily, 3 (the regioisomer of 4) and its racemic derivatives (cis-2,3-dihydrobenzofurans) were previously described to exacerbate such episodes, pointing to their positive allosteric modulation (PAMs) of the same receptor.
(© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)
Databáze: MEDLINE
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