title: Novel Potent N-Methyl-d-aspartate (NMDA) Receptor Antagonists or σ1 Receptor Ligands Based on Properly Substituted 1,4-Dioxane Ring.
abstract: Two series of 1,4-dioxanes (4-11 and 12-19) were rationally designed and prepared to interact either with the phencyclidine (PCP) binding site of the N-methyl-d-aspartate (NMDA) receptor or with σ1 receptors, respectively. The biological profiles of the novel compounds were assessed using radioligand binding assays, and the compounds with the highest affinities were investigated for their functional activity. The results were in line with the available pharmacophore models and highlighted that the 1,4-dioxane scaffold is compatible with potent antagonist activity at NMDA receptor or high affinity for σ1 receptors. The primary amines 6b and 7 bearing a cyclohexyl and a phenyl ring or two phenyl rings in position 6, respectively, were the most potent noncompetitive antagonists at the NMDA receptor with IC50 values similar to those of the dissociative anesthetic (S)-(+)-ketamine. The 5,5-diphenyl substitution associated with a benzylaminomethyl moiety in position 2, as in 18, favored the interaction with σ1 receptors.
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino , Via S. Agostino 1, 62032 Camerino, Italy.|Institut für Pharmazeutische und Medizinische Chemie, Universität Münster , Corrensstraße 48, 48149 Münster, Germany.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bonifazi
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Del Bello
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Mammoli
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Piergentili
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Petrelli
authors.affiliation: Scuola di Scienze e Tecnologie, Università di Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cimarelli
authors.affiliation: Scuola di Scienze e Tecnologie, Università di Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Pellei
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Universität Münster , Corrensstraße 48, 48149 Münster, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Universität Münster , Corrensstraße 48, 48149 Münster, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , V.le delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barocelli
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , V.le delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Bertoni
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , V.le delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Flammini
authors.affiliation: Scuola di Bioscienze e Medicina Veterinaria, Università di Camerino , via Madonna delle Carceri 9, 62032 Camerino, Italy.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Amantini
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino , Via Madonna delle Carceri 9, 62032 Camerino, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Nabissi
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino , Via Madonna delle Carceri 9, 62032 Camerino, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Santoni
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano , Via Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Vistoli
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Wilma
authors.initials: W
authors.lastname: Quaglia
mesh_terms: D000700:Analgesics / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001665:Binding Sites; D004146:Dioxanes / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D010146:Pain / Q000188:drug therapy; D010622:Phencyclidine / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017480:Receptors, sigma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D000700:Analgesics; D004146:Dioxanes; D008024:Ligands; D010622:Phencyclidine; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C025223:1,4-dioxane