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

Eva Prchalová, Niyada Hin, Ajit G. Thomas, Vijayabhaskar Veeravalli, Justin Ng, Jesse Alt, Rana Rais, Camilo Rojas, Zhe Li, Hiroe Hihara, Mika Aoki, Kyoko Yoshizawa, Tomoki Nishioka, Shuichi Suzuki, Theresa Kopajtic, Sheena Chatrath, Qin Liu, Xinzhong Dong, Barbara S. Slusher, Takashi Tsukamoto

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)8631-8641
Number of pages11
JournalJournal of medicinal chemistry
Volume62
Issue number18
DOIs
StatePublished - Sep 26 2019

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G-Protein-Coupled Receptors
HEK293 Cells
Opioid Receptors
Sensory Receptor Cells
Analgesics
Spinal Cord
Pain
benzamidine
1-aminoisoquinoline
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Discovery of Benzamidine- And 1-Aminoisoquinoline-Based Human MAS-Related G-Protein-Coupled Receptor X1 (MRGPRX1) Agonists. / Prchalová, Eva; Hin, Niyada; Thomas, Ajit G.; Veeravalli, Vijayabhaskar; Ng, Justin; Alt, Jesse; Rais, Rana; Rojas, Camilo; Li, Zhe; Hihara, Hiroe; Aoki, Mika; Yoshizawa, Kyoko; Nishioka, Tomoki; Suzuki, Shuichi; Kopajtic, Theresa; Chatrath, Sheena; Liu, Qin; Dong, Xinzhong; Slusher, Barbara S.; Tsukamoto, Takashi.

In: Journal of medicinal chemistry, Vol. 62, No. 18, 26.09.2019, p. 8631-8641.

Research output: Contribution to journalArticle

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 2019, 'Discovery of Benzamidine- And 1-Aminoisoquinoline-Based Human MAS-Related G-Protein-Coupled Receptor X1 (MRGPRX1) Agonists', Journal of medicinal chemistry, vol. 62, no. 18, pp. 8631-8641. https://doi.org/10.1021/acs.jmedchem.9b01003
Prchalová, Eva ; Hin, Niyada ; Thomas, Ajit G. ; Veeravalli, Vijayabhaskar ; Ng, Justin ; Alt, Jesse ; Rais, Rana ; Rojas, Camilo ; Li, Zhe ; Hihara, Hiroe ; Aoki, Mika ; Yoshizawa, Kyoko ; Nishioka, Tomoki ; Suzuki, Shuichi ; Kopajtic, Theresa ; Chatrath, Sheena ; Liu, Qin ; Dong, Xinzhong ; Slusher, Barbara S. ; Tsukamoto, Takashi. / Discovery of Benzamidine- And 1-Aminoisoquinoline-Based Human MAS-Related G-Protein-Coupled Receptor X1 (MRGPRX1) Agonists. In: Journal of medicinal chemistry. 2019 ; Vol. 62, No. 18. pp. 8631-8641.
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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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AU - Thomas, Ajit G.

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AU - Liu, Qin

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