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 (â8.7 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.
Bibliographical noteFunding Information:
This research was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R35GM124718, the National Institutes of Health under award number R01EY028103, and the Foundation Fighting Blindness award number TA-NMT-0617-021-AUG.
Our labs disclosed phenethylamine-containing heterocycles that were potent and selective G protein-coupled receptor (GPCR) ligands. These heterocycles were synthesized via tandem Friedel–Crafts alkylation (a). The compounds’ activity was investigated due to the phenethylamine backbone. Initial assays, using racemic samples, identified three selective ligands for the 5-HT, 5-HT, or σ receptors (, compounds 5 – 7 , respectively). The ligand (±)- 7 ’s activity was supported by cellular assays. This inspired a more focused study aiming to improve the σ ligand. Here, a family of 36 σ receptor ligands was synthesized in a nonracemic form. Several ligands demonstrated improved affinity. The lead compound’s activity was assessed by oxidative stress assays for neuroprotection. 2B 7 1 1 1
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