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

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

  • J Med Chem. 2019 Sep 26;62(18):8631-8641. doi: 10.1021/acs.jmedchem.9b01003.
Eva Prchalová,  Niyada Hin,  Ajit G Thomas,  Vijayabhaskar Veeravalli,  Justin Ng,  Jesse Alt,  Rana Rais,  Camilo Rojas,  Zhe Li,  Hiroe Hihara 1,  Mika Aoki 1,  Kyoko Yoshizawa 1,  Tomoki Nishioka 1,  Shuichi Suzuki 1,  Theresa Kopajtic 2,  Sheena Chatrath 3,  Qin Liu 3,  Xinzhong Dong,  Barbara S Slusher,  Takashi Tsukamoto
Affiliations

Affiliations

  • 1 Tsukuba Research Laboratories , Eisai Co., Ltd. , Tsukuba , Ibaraki 300-2635 , Japan.
  • 2 Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit , National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , Baltimore , Maryland 21224 , United States.
  • 3 Department of Anesthesiology and Center for the Study of Itch , Washington University School of Medicine , St. Louis , Missouri 63110 , United States.
PMID: 31498617 DOI: 10.1021/acs.jmedchem.9b01003
Abstract

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 (5a) and 4-(2-(butylsulfonamido)-4-methylphenoxy)benzimidamide (11a), 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, N-(2-(1-aminoisoquinolin-6-yloxy)-4-methylphenyl)-2-methoxybenzenesulfonamide (16), not only devoid of positively charged amidinium group but also with superior selectivity over opioid receptors. In mice, compound 16 displayed favorable distribution to the spinal cord, the presumed site of action for the MRGPRX1-mediated analgesic effects.

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