title: Synthesis, modelling and biological characterization of 3-substituted-1H-indoles as ligands of GluN2B-containing N-methyl-d-aspartate receptors.
abstract: A three-step synthetic pathway has been employed to synthesize a small library of 2-(4-arylpiperidin-1-yl)-1-(1H-indol-3-yl)ethanone and 2-(4-arylpiperidin-1-yl)-1-(1H-indol-3-yl)ethane-1,2-dione derivatives that have been screened in [(3)H]ifenprodil competition binding assay. Some compounds exhibited significant binding affinity at nanomolar concentration, the most active being ligand 35 (IC50=5.5nM). Docking experiments suggested the main interactions between 35 and GluN2B-containing NMDA receptors. Notably, the compound 35 reduced NMDA-mediated excitatory post-synaptic currents recorded in mouse hippocampal slices indicating antagonistic effects (50nM). Moreover, the compound 35 has shown antioxidant effects in a preliminary screening, thus suggesting that it might be considered prototype for future drug development of novel 'dual target' neuroprotective agents.
authors.affiliation: Dipartimento di Scienze del Farmaco e Prodotti per la Salute, Università di Messina, Viale Annunziata, I-98168 Messina, Italy. Electronic address: rgitto@unime.it.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Gitto
authors.affiliation: Dipartimento di Scienze del Farmaco e Prodotti per la Salute, Università di Messina, Viale Annunziata, I-98168 Messina, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: De Luca
authors.affiliation: Dipartimento di Scienze del Farmaco e Prodotti per la Salute, Università di Messina, Viale Annunziata, I-98168 Messina, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Ferro
authors.affiliation: Dipartimento di Scienze della Salute, Università Magna Graecia, Viale Europa Località Germaneto, I-88100 Catanzaro, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Russo
authors.affiliation: Dipartimento di Scienze della Salute, Università Magna Graecia, Viale Europa Località Germaneto, I-88100 Catanzaro, Italy.
authors.forename: Giovambattista
authors.initials: G
authors.lastname: De Sarro
authors.affiliation: Dipartimento di Biomedicina Clinica e Molecolare, Sezione di Farmacologia e Biochimica, Università di Catania, Viale Andrea Doria 6, I-95125 Catania, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Chisari
authors.affiliation: Dipartimento di Scienze Bio-Mediche, Sezione di Fisiologia, Università di Catania, Viale Andrea Doria 6, I-95125 Catania, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Ciranna
authors.affiliation: Departamento de Química Orgánica I, Universidad de Alcalá, Campus Universitario, 28871 Alcalá de Henares, Madrid, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Alvarez-Builla
authors.affiliation: Departamento de Química Orgánica I, Universidad de Alcalá, Campus Universitario, 28871 Alcalá de Henares, Madrid, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Alajarin
authors.affiliation: Dipartimento di Scienze del Farmaco e Prodotti per la Salute, Università di Messina, Viale Annunziata, I-98168 Messina, Italy.
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Buemi
authors.affiliation: Dipartimento di Scienze del Farmaco e Prodotti per la Salute, Università di Messina, Viale Annunziata, I-98168 Messina, Italy.
authors.forename: Alba
authors.initials: A
authors.lastname: Chimirri
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D060326:Chemistry Techniques, Synthetic; D006624:Hippocampus / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry*; D008024:Ligands; D051379:Mice; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010880:Piperidines / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D000975:Antioxidants; D007211:Indoles; D008024:Ligands; C121001:NR2B NMDA receptor; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D054852:Small Molecule Libraries; C010739:ifenprodil
keywords: GluN2B; Glutamate; Ifenprodil; Indoles; Molecular docking