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Papers of the Week

Papers: 7 Sep 2019 - 13 Sep 2019

Animal Studies, Human Studies, Pharmacology/Drug Development

2019 Sep 26

J Med Chem



Discovery of Benzamidine- and 1-Aminoisoquinoline-Based Human MAS-Related G-Protein-Coupled Receptor X1 (MRGPRX1) Agonists.


Prchalová E, Hin N, Thomas AG, Veeravalli V, Ng J, Alt J, Rais R, Rojas C, Li Z, Hihara H, Aoki M, Yoshizawa K, Nishioka T, Suzuki S, Kopajtic T, Chatrath S, Liu Q, Dong X, Slusher BS, Tsukamoto T
J Med Chem. 2019 Sep 26; 62(18):8631-8641.
PMID: 31498617.


Mas-related G-protein-coupled receptor X1 (MRGPRX1) is a human sensory neuron-specific receptor and has been actively investigated as a therapeutic target for the treatment of pain. By use of two HTS screening hit compounds, 4-(4-(benzyloxy)-3-methoxybenzylamino)benzimidamide () and 4-(2-(butylsulfonamido)-4-methylphenoxy)benzimidamide (), as molecular templates, a series of human MRGPRX1 agonists were synthesized and evaluated for their agonist activity using HEK293 cells stably transfected with human MrgprX1. Conversion of the benzamidine moiety into a 1-aminoisoquinoline moiety carried out in the later stage of structural optimization led to the discovery of a highly potent MRGPRX1 agonist, -(2-(1-aminoisoquinolin-6-yloxy)-4-methylphenyl)-2-methoxybenzenesulfonamide (), not only devoid of positively charged amidinium group but also with superior selectivity over opioid receptors. In mice, compound displayed favorable distribution to the spinal cord, the presumed site of action for the MRGPRX1-mediated analgesic effects.