1,4-Dioxane nucleus as a suitable scaffold in the building of ligands interacting with NMDA and σ1 receptors

The dissociative anaesthetics dexoxadrol and etoxadrol behave as potent non-competitive NMDA receptor antagonists. Recently, it has been demonstrated that their piperidine ring was not necessary for high NMDA receptor affinity because its replacement with aminomethyl chain led to potent NMDA receptor antagonists. Ring and side chain homologues of aminomethyl analogues of dexoxadrol and etoxadrol resulted in 1,3-dioxane compounds which showed high NMDA or σ1 receptor affinity, depending on the substitution at the nitrogen atom and the distance between the heterocycle oxygen atoms and the amino function.[2] Among these compounds, the derivative 1 behaved as the most potent NMDA antagonist whereas derivatives 2 and 3 did not interact with the NMDA receptor, but showed high affi nity for σ1 receptors (Figure 1).[2] To extend the structure-activity relationship (SAR) study and get further information about the role played by the heterocycle oxygen atoms and the distances between the fragments constituting the pharmacophores, in the present study two series of analogues of 1-3 are presented. All the novel compounds bear the 1,4-dioxane ring which, differently substituted in positions 2 and 5 or 6, has already proved to be a suitable scaffold for building ligands selectively targeting different receptors. The first series of compounds, designed to interact with NMDA receptor, is characterized by an aminomethyl or 2-aminoethyl side chain in position 2 and alkyl and/or aryl substituents in positions 5 or 6 of the 1,4-dioxane ring. In the second series the N-benzyl substituent should favour the selective interaction with σ1 receptors.The obtained results confi rm the bioversatility ofthe 1,4-dioxane scaffold, highlighting that it is suitable for ligands endowed with potent antagonist activity at NMDA or σ1 receptors, depending on the substituents in positions 5 or 6 and the amino function in position 2. Moreover, computational studies were conducted to evaluate whether preferred conformations adopted by the two dioxane rings and/or stereo-electronic properties and/or the distances between the pharmacophoric features were responsible for different SARs obtained for 1,3- and 1,4-dioxane series.