title: From NMDA receptor antagonists to discovery of selective σ₂ receptor ligands.
abstract: Following previous studies focused on the search for new molecules targeting GluN2B-containing NMDA, a small series of 1-(1H-indol-3-yl)-2-(4-phenylpiperidin-1-yl)ethanone derivatives has been synthesized by using Microwave Assisted Organic Synthesis (MAOS). Given that GluN2B ligands frequently exert off-target effects we also tested their affinity towards sigma receptors. Binding assay revealed that only the 1-(5-hydroxy-1H-indol-3-yl)-2-(4-phenylpiperidin-1-yl)ethanone (7a) retained GluN2B affinity. Interestingly, the 5-methoxyindoles 5a and 6a were efficient and selective ligands toward σ₂ receptor (Ki values of 10nM and 20 nM, respectively). Thus, in this case the discovery of new σ₂ receptor selective ligands was an unexpected result emerging from the screening of cross-activity against other CNS receptors.
authors.affiliation: Dipartimento di Scienze del Farmaco e dei 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 dei 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 dei 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 Chimiche, Viale Ferdinando Stagno d'Alcontres, I-98166 Messina, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Scala
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, Viale Andrea Doria 6, I-95125 Catania, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Ronsisvalle
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, Viale Andrea Doria 6, I-95125 Catania, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Parenti
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, Viale Andrea Doria 6, I-95125 Catania, Italy.
authors.forename: Orazio
authors.initials: O
authors.lastname: Prezzavento
authors.affiliation: Dipartimento di Scienze del Farmaco e dei 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 dei Prodotti per la Salute, Università di Messina, Viale Annunziata, I-98168 Messina, Italy.
authors.forename: Alba
authors.initials: A
authors.lastname: Chimirri
mesh_terms: D001665:Binding Sites; D018698:Glutamic Acid / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017480:Receptors, sigma / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; D018698:Glutamic Acid
keywords: GluN2B/NMDA; Glutamate; Ifenprodil; Indoles; Sigma receptor