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

Matthew R Porter; Haiyan Xiao; Sanjay Maity; Nora Vail; Sylvia B Smith; Joseph J Topczewski

doi:10.1021/acsomega.0c05117

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

ACS Omega. 2020 Dec 11;5(50):32724-32737. doi: 10.1021/acsomega.0c05117. eCollection 2020 Dec 22.

Authors

Matthew R Porter¹, Haiyan Xiao^{2

3}, Sanjay Maity¹, Nora Vail¹, Sylvia B Smith^{2

3

4}, Joseph J Topczewski¹

Affiliations

¹ Department of Chemistry, University of Minnesota Twin Cities, Minneapolis, Minnesota 55455, United States.
² Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia 30912, United States.
³ James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, Georgia 30912, United States.
⁴ Department of Ophthalmology, Medical College of Georgia at Augusta University, Augusta, Georgia 30912, United States.

Abstract

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 K _i range (∼8.7 pK _i). 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.

Abstract

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