1,4-Dioxane, a Suitable Scaffold for the Development of Novel M₃ Muscarinic Receptor Antagonists

In this study the modulation of the pharmacological profile from agonist to antagonist was successfully obtained by replacing the methyl group in position 6 of the 1,4-dioxane scaffold of the potent M₂/M₃ muscarinic agonist <b>1</b> with bulkier groups. In particular, the 6,6-diphenyl substitution provided the potent M₃ preferring antagonist (±)-<b>17</b>, which in in vivo study proved to be effective in reducing the volume-induced contractions of rat urinary bladder and was devoid of cardiovascular effects

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

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