posted on 2015-11-12, 00:00authored byAlessandro 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 (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.