Enhanced Affinity for 3‑Amino-Chromane-Derived σ₁ Receptor Ligands

The σ1 receptor is implicated in regulating a diverse range of physiology and is a target for developing therapies for cancer, pain management, neural degradation, and COVID-19. This report describes 36 phenethylamine-containing 3-amino-chromane ligands, which bind to σ1 with low nM affinities. The family consists of 18 distinct compounds and each enantiomer was independently assayed. Three compounds with the greatest affinity bind in the 2 nM Ki range (∼8.7 pKi). Furthermore, ligands with the (3R,4R) absolute stereochemistry on the 3-amino-chromane core have a higher affinity and greater σ1 versus TMEM97 selectivity. The most promising ligands were assayed in 661W cells, which did not show significant protective effects.