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ChemMedChem. 2015 Jan;10(1):57-61. doi: 10.1002/cmdc.201402277. Epub 2014 Sep 10.

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

Author information

1
Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt Specialized Chemistry Center (MLPCN), Vanderbilt University Medical Center, Nashville, TN 37232-6600 (USA).

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.

KEYWORDS:

ML382; MLPCN; MrgX1; chronic pain; molecular probes; positive allosteric modulators

PMID:
25209672
PMCID:
PMC4276534
DOI:
10.1002/cmdc.201402277
[Indexed for MEDLINE]
Free PMC Article

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