Dataset Information

Enhanced Affinity for 3-Amino-Chromane-Derived ?₁ Receptor Ligands.

ABSTRACT: The ?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 ?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 pK _i). Furthermore, ligands with the (3R,4R) absolute stereochemistry on the 3-amino-chromane core have a higher affinity and greater ?₁ versus TMEM97 selectivity. The most promising ligands were assayed in 661W cells, which did not show significant protective effects.

SUBMITTER: Porter MR

PROVIDER: S-EPMC7758967 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Porter Matthew R MR Xiao Haiyan H Maity Sanjay S Vail Nora N Smith Sylvia B SB Topczewski Joseph J JJ

ACS omega 20201211 50

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 (∼ ...[more]

PMID: 33376910

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Project description:Outbreaks of emerging infections, such as COVID-19 pandemic especially, confront health professionals with the unique challenge of treating patients. With no time to discover new drugs, repurposing of approved drugs or in clinical development is likely the only solution. Replication of coronaviruses (CoVs) occurs in a modified membranous compartment derived from the endoplasmic reticulum (ER), causes host cell ER stress and activates pathways to facilitate adaptation of the host cell machinery to viral needs. Accordingly, modulation of ER remodeling and ER stress response might be pivotal in elucidating CoV-host interactions and provide a rationale for new therapeutic, host-based antiviral approaches. The sigma-1 receptor (Sig-1R) is a ligand-operated, ER membrane-bound chaperone that acts as an upstream modulator of ER stress and thus a candidate host protein for host-based repurposing approaches to treat COVID-19 patients. Sig-1R ligands are frequently identified in in vitro drug repurposing screens aiming to identify antiviral compounds against CoVs, including severe acute respiratory syndrome CoV-2 (SARS-CoV-2). Sig-1R regulates key mechanisms of the adaptive host cell stress response and takes part in early steps of viral replication. It is enriched in lipid rafts and detergent-resistant ER membranes, where it colocalizes with viral replicase proteins. Indeed, the non-structural SARS-CoV-2 protein Nsp6 interacts with Sig-1R. The activity of Sig-1R ligands against COVID-19 remains to be specifically assessed in clinical trials. This review provides a rationale for targeting Sig-1R as a host-based drug repurposing approach to treat COVID-19 patients. Evidence gained using Sig-1R ligands in unbiased in vitro antiviral drug screens and the potential mechanisms underlying the modulatory effect of Sig-1R on the host cell response are discussed. Targeting Sig-1R is not expected to reduce dramatically established viral replication, but it might interfere with early steps of virus-induced host cell reprogramming, aid to slow down the course of infection, prevent the aggravation of the disease and/or allow a time window to mature a protective immune response. Sig-1R-based medicines could provide benefit not only as early intervention, preventive but also as adjuvant therapy.

Dataset Information

Enhanced Affinity for 3-Amino-Chromane-Derived ?₁ Receptor Ligands.

Publications

Enhanced Affinity for 3-Amino-Chromane-Derived σ<sub>1</sub> Receptor Ligands.

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OmicsDI is part of the ELIXIR infrastructure

Dataset Information

Enhanced Affinity for 3-Amino-Chromane-Derived ?1 Receptor Ligands.

Publications

Enhanced Affinity for 3-Amino-Chromane-Derived σ<sub>1</sub> Receptor Ligands.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Enhanced Affinity for 3-Amino-Chromane-Derived ?₁ Receptor Ligands.