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.
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt Specialized Chemistry Center (MLPCN), Vanderbilt University Medical Center, Nashville, TN 37232-6600 (USA).
authors.forename: Wandong
authors.initials: W
authors.lastname: Wen
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.forename: Pang-Yen
authors.initials: PY
authors.lastname: Tseng
authors.forename: Owen B
authors.initials: OB
authors.lastname: McManus
authors.forename: Meng
authors.initials: M
authors.lastname: Wu
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: Xinzhong
authors.initials: X
authors.lastname: Dong
authors.forename: Corey R
authors.initials: CR
authors.lastname: Hopkins
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001549:Benzamides / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D051379:Mice; D011485:Protein Binding; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D001549:Benzamides; D043562:Receptors, G-Protein-Coupled; D013449:Sulfonamides; C000600806:ML382 compound; C470192:Mrgprx1 protein, mouse; C510803:mas-related gene-X1 receptor, human
keywords: ML382; MLPCN; MrgX1; chronic pain; molecular probes; positive allosteric modulators