Development of Novel Alkoxyisoxazoles as Sigma‑1 Receptor Antagonists with Antinociceptive Efficacy

A novel series of
sigma (σ) receptor ligands based on an
alkoxyisoxazole scaffold has been designed and synthesized. Preliminary
receptor binding assays identified highly potent (Ki < 1 nM) and selective σ1 ligands devoid of
binding interactions with the monoamine transporters DAT, NET, and
SERT. In particular, compound 53 was shown to possess
significant antinociceptive activity in the mouse formalin-induced
inflammation pain model when administered intraperitoneally at 40
and 80 mg/kg. Initial pharmacokinetics evaluation indicated an excellent
brain exposure following oral dosing in mice, suggesting that further
investigation into the use of alkoxyisoxazoles as σ1 ligands
for antinociception is warranted. This study supports the notion that
selective σ1 antagonism could be a useful strategy in the development
of novel antipain therapy.