Synthesis and Structure–Activity Relationship Study of a New Series of Selective σ₁ Receptor Ligands for the Treatment of Pain: 4‑Aminotriazoles

The synthesis and pharmacological activity of a new series of 4-aminotriazoles as potent σ₁ receptor (σ₁R) ligands are reported. The compounds were prepared using a 4–5-step process, involving as a key step a click chemistry reaction between ynamides and azides. The most active compounds exhibited nanomolar potency for the σ₁R, and the selectivity over the σ₂R was improved on decreasing the central amine basicity. It was concluded that in order to achieve good σ₁R potency a minimum lipophilicity was required, while limiting to a defined range of cLog<i>P</i> avoided human ether-a-go-go-related gene channel inhibition. This made the most interesting derivatives to be concentrated in a narrow margin of lipophilicity. Among them, compound <b>13g</b> exhibited the most potent in vivo antinociceptive properties, which are indicative of its antagonist character