Novel Potent <i>N</i>‑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 (<b>4</b>–<b>11</b> and <b>12</b>–<b>19</b>) were rationally designed and prepared to interact either with the phencyclidine (PCP) binding site of the <i>N</i>-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 <b>6b</b> and <b>7</b> 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 (<i>S</i>)-(+)-ketamine. The 5,5-diphenyl substitution associated with a benzylaminomethyl moiety in position 2, as in <b>18</b>, favored the interaction with σ₁ receptors