3-Amino-chromanes and Tetrahydroquinolines as Selective 5-HT2B, 5-HT7, or σ1 Receptor Ligands

The phenethylamine backbone is a privileged substructure found in a wide variety of G protein-coupled receptor (GPCR) ligands. This includes both endogenous neurotransmitters and active pharmaceutical agents. More than 20 structurally unique heterocyclic phenethylamine derivatives were broadly evaluated for GPCR affinity. Selective ligands for the 5-HT2B, 5-HT7 and sigma(1) receptors were identified, each with low nanomolar binding affinities. The sigma(1) receptor affinity was supported in a cellular assay that provided evidence for increased cell survival under oxidative stress.