Discovery and characterization of 2-(cyclopropanesulfonamido)-n-(2-ethoxyphenyl)benzamide, ML382: A potent and selective positive allosteric modulator of MrgX1

Wandong Wen; Yan Wang; Zhe Li; Pang Yen Tseng; Owen B. McManus; Meng Wu; Min Li; Craig W. Lindsley; Xinzhong Dong; Corey R. Hopkins

doi:10.1002/cmdc.201402277

Discovery and characterization of 2-(cyclopropanesulfonamido)-n-(2-ethoxyphenyl)benzamide, ML382: A potent and selective positive allosteric modulator of MrgX1

Wandong Wen, Yan Wang, Zhe Li, Pang Yen Tseng, Owen B. McManus, Meng Wu, Min Li, Craig W. Lindsley, Xinzhong Dong, Corey R. Hopkins

School of Medicine

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

3 Scopus citations

Abstract

Previous studies have shown that the activation of mouse MrgC11, a G-protein-coupled receptor, by its peptide ligand BAM8-22 can inhibit chronic pain. A large-scale screen has been carried out to isolate small-molecule allosteric agonists of MrgX1, the human homologue of MrgC11. The goal of this study is to improve the efficacy and potency of positive allosteric modulators (PAMs) with therapeutic implications in combating chronic pain. Herein we report an iterative parallel synthesis effort and a structure-activity relationship study of a series of arylsulfonamides which led to the discovery of the first PAM of MrgX1, ML382.

Original language	English (US)
Pages (from-to)	57-61
Number of pages	5
Journal	ChemMedChem
Volume	10
Issue number	1
DOIs	https://doi.org/10.1002/cmdc.201402277
State	Published - Jan 2015

Keywords

Chronic pain
ML382
MLPCN
Molecular probes
MrgX1
Positive allosteric modulators

ASJC Scopus subject areas

Drug Discovery
General Pharmacology, Toxicology and Pharmaceutics
Molecular Medicine
Biochemistry
Pharmacology
Organic Chemistry

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title = "Discovery and characterization of 2-(cyclopropanesulfonamido)-n-(2-ethoxyphenyl)benzamide, ML382: A potent and selective positive allosteric modulator of MrgX1",

abstract = "Previous studies have shown that the activation of mouse MrgC11, a G-protein-coupled receptor, by its peptide ligand BAM8-22 can inhibit chronic pain. A large-scale screen has been carried out to isolate small-molecule allosteric agonists of MrgX1, the human homologue of MrgC11. The goal of this study is to improve the efficacy and potency of positive allosteric modulators (PAMs) with therapeutic implications in combating chronic pain. Herein we report an iterative parallel synthesis effort and a structure-activity relationship study of a series of arylsulfonamides which led to the discovery of the first PAM of MrgX1, ML382.",

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T2 - A potent and selective positive allosteric modulator of MrgX1

AU - Wen, Wandong

AU - Wang, Yan

AU - Li, Zhe

AU - Tseng, Pang Yen

AU - McManus, Owen B.

AU - Wu, Meng

AU - Li, Min

AU - Lindsley, Craig W.

AU - Dong, Xinzhong

AU - Hopkins, Corey R.

PY - 2015/1

Y1 - 2015/1

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AB - Previous studies have shown that the activation of mouse MrgC11, a G-protein-coupled receptor, by its peptide ligand BAM8-22 can inhibit chronic pain. A large-scale screen has been carried out to isolate small-molecule allosteric agonists of MrgX1, the human homologue of MrgC11. The goal of this study is to improve the efficacy and potency of positive allosteric modulators (PAMs) with therapeutic implications in combating chronic pain. Herein we report an iterative parallel synthesis effort and a structure-activity relationship study of a series of arylsulfonamides which led to the discovery of the first PAM of MrgX1, ML382.

KW - Chronic pain

KW - ML382

KW - MLPCN

KW - Molecular probes

KW - MrgX1

KW - Positive allosteric modulators

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Discovery and characterization of 2-(cyclopropanesulfonamido)-n-(2-ethoxyphenyl)benzamide, ML382: A potent and selective positive allosteric modulator of MrgX1

Abstract

Keywords

ASJC Scopus subject areas

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