Mas-related G-protein coupled receptor X1 (MRGPRX1) is a human sensory neuron-specific receptor and has gained increasing interest as a therapeutic target for the treatment of pain. Positive allosteric modulators (PAMs) of MRGPRX1 are particularly promising as they have the potential to preferentially activate the receptors at the central terminals of primary sensory neurons, and minimize itch side effects caused by the activation of these receptors on the peripheral nerves. Herein, we present the discovery of potent, orally available, thieno[2,3-<i>d</i>]pyrimidine-based MRGPRX1 PAMs with efficacy in a preclinical pain model, demonstrating the therapeutic potential of MRGPRX1 PAMs in treating patients suffering from neuropathic pain.

Thieno[2,3-<i>d</i>]pyrimidine-based positive allosteric modulators of human MAS-related G protein-coupled receptor X1 (MRGPRX1)

ACS Spring 2022

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Thieno[2,3-d]pyrimidine-based positive allosteric modulators of human MAS-related G protein-coupled receptor X1 (MRGPRX1)