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

Synthesis and Biological Evaluation of a New Series of Hexahydro‑2<i>H</i>‑pyrano[3,2‑<i>c</i>]quinolines as Novel Selective σ₁ Receptor Ligands

The synthesis and pharmacological activity of a new series of hexahydro-2<i>H</i>-pyrano­[3,2-<i>c</i>]­quinoline derivatives as potent σ₁ receptor (σ₁R) ligands are reported. This family, which does not contain the highly basic amino group usually present in other σ₁R ligands, showed high selectivity over the σ₂ receptor (σ₂R). The activity was shown to reside in only one of the four possible diastereoisomers, which exhibited a perfect match with known σ₁R pharmacophores. A hit to lead program based on a high-throughput screening hit (<b>8a</b>) led to the identification of compound <b>32c</b>, with substantially improved activity and physicochemical properties. Compound <b>32c</b> also exhibited a good ADMET (absorption, distribution, metabolism, excretion, toxicity) profile and was identified as a σ₁R antagonist on the basis of its analgesic activity in the mouse capsaicin and formalin models of neurogenic pain