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Novel Potent N‑Methyl‑d‑aspartate (NMDA) Receptor Antagonists or σ1 Receptor Ligands Based on Properly Substituted 1,4-Dioxane Ring

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posted on 2015-11-12, 00:00 authored by Alessandro Bonifazi, Fabio Del Bello, Valerio Mammoli, Alessandro Piergentili, Riccardo Petrelli, Cristina Cimarelli, Maura Pellei, Dirk Schepmann, Bernhard Wünsch, Elisabetta Barocelli, Simona Bertoni, Lisa Flammini, Consuelo Amantini, Massimo Nabissi, Giorgio Santoni, Giulio Vistoli, Wilma Quaglia
Two series of 1,4-dioxanes (411 and 1219) 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.

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