The σ 1 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 σ 1 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 K i range (∼8.7 p K i). Furthermore, ligands with the (3 R,4 R) absolute stereochemistry on the 3-amino-chromane core have a higher affinity and greater σ 1 versus TMEM97 selectivity. The most promising ligands were assayed in 661W cells, which did not show significant protective effects.