Enhanced Affinity for 3-Amino-Chromane-Derived σ1Receptor 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 σ₁Receptor Ligands

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

Chemistry (Twin Cities)

Research output: Contribution to journal › Article › peer-review

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 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.

Original language	English (US)
Pages (from-to)	32724-32737
Number of pages	14
Journal	ACS Omega
Volume	5
Issue number	50
DOIs	https://doi.org/10.1021/acsomega.0c05117
State	Published - Dec 22 2020

Bibliographical note

Funding 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.

Funding Information:
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

Publisher Copyright:
© 2020 American Chemical Society.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access

10.1021/acsomega.0c05117

OpenUrl availability

Full text

Cite this

@article{50a4f548eb3844228b099c786cac400a,

title = "Enhanced Affinity for 3-Amino-Chromane-Derived σ1Receptor Ligands",

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 Ki range ({\^a}8.7 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.",

author = "Porter, {Matthew R.} and Haiyan Xiao and Sanjay Maity and Nora Vail and Smith, {Sylvia B.} and Topczewski, {Joseph J.}",

note = "Funding 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. Funding Information: 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{\textquoteright} 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 {\textquoteright}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{\textquoteright}s activity was assessed by oxidative stress assays for neuroprotection. 2B 7 1 1 1 Publisher Copyright: {\textcopyright} 2020 American Chemical Society.",

year = "2020",

month = dec,

day = "22",

doi = "10.1021/acsomega.0c05117",

language = "English (US)",

volume = "5",

pages = "32724--32737",

journal = "ACS Omega",

issn = "2470-1343",

publisher = "American Chemical Society",

number = "50",

}

TY - JOUR

T1 - Enhanced Affinity for 3-Amino-Chromane-Derived σ1Receptor Ligands

AU - Porter, Matthew R.

AU - Xiao, Haiyan

AU - Maity, Sanjay

AU - Vail, Nora

AU - Smith, Sylvia B.

AU - Topczewski, Joseph J.

N1 - Funding 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. Funding Information: 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 Publisher Copyright: © 2020 American Chemical Society.

PY - 2020/12/22

Y1 - 2020/12/22

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85098973241&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85098973241&partnerID=8YFLogxK

U2 - 10.1021/acsomega.0c05117

DO - 10.1021/acsomega.0c05117

M3 - Article

C2 - 33376910

AN - SCOPUS:85098973241

SN - 2470-1343

VL - 5

SP - 32724

EP - 32737

JO - ACS Omega

JF - ACS Omega

IS - 50

ER -