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

Abstract

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 cLogP 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 13g exhibited the most potent in vivo antinociceptive properties, which are indicative of its antagonist character.

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

“…Compound 102 was the product of continued research by Esteve for σ1R antagonists for the treatment of pain . The morpholine moiety proved again to be crucial in this series of compounds, as it was a key feature of the compound's potency on σ1R ( K i = 61 nM), providing a moderately basic nitrogen atom required for selectivity on σ1R over σ2R ( K i > 10 000 nM), while it contributed towards the desirable lipophilicity.…”

Investigational sigma-1 receptor antagonists for the treatment of pain

“…The indene scaffold was also a good core for providing subtype selective s 1 R ligands such as 19 [77] and 20 [78,79], in a similar way to pyrazole derivatives 21 [80] and 22 [81]. Compound 23, identified from a scaffold hopping approach over 32, provided a good selectivity and high in vivo potency in three pain models (formalin, capsaicin and partial sciatic nerve ligation) in mice [82][83][84]. Also, structurally related to 32, a patent application of the tricyclic triazoles represented by 24 has recently been published [85], reinforcing the interest in this previously reported framework [86].…”

Molecular mechanisms underlying the involvement of the sigma-1 receptor in methamphetamine-mediated microglial polarization

“…Sigma receptors are classified into two subtypes, sigma-1 and sigma-2 receptors 16 . The sigma-1 receptor, which is a unique ligand-regulated molecular chaperone, is related to many conditions, such as stroke 17 , pain 18 and HIV infection 19 . The sigma-2 receptor plays a role in pathogenesis by modulating cell proliferation 20 .…”