ML382

ML382 is a potent and selective MRGPRX1 (Mas-related G protein-coupled receptor X1, MrgX1) positive allosteric modulator, with an EC₅₀ of 190 nM^[1]. IC50 & Target: EC50: 190 nM (MRGPRX1)^[1] In Vitro: In the absence of ML382, the IC₅₀ for BAM8-22 inhibition of I_Ca is 0.66 ± 0.05 μM. In the presence of 0.1 μM, 1 μM, 10 μM, and 30 μM ML382, BAM8-22 IC₅₀ is reduced to 0.43 ± 0.02 μM, 0.25 ± 0.02 μM, 0.06 ± 0.01 μM, and 0.08 ± 0.01 μM, respectively. A lower IC₅₀ generally indicates a higher potency; thus, ML382 dose-dependently increases the potency of BAM8–22, further demonstrating that ML382 is a positive allosteric modulator of MRGPRX1^[1]. In Vivo: ML382 (5 μM) significantly increases inhibition of I_Ca by a low concentration of BAM8–22 (0.5 μM) in DRG neurons from MrgprX1 mice. ML382 enhances the inhibition of spinal synaptic transmission by BAM8-22 in MrgprX1 mice. ML382 (25 μM, 125 μM, and 250 μM; 5 μL; i.th.;) dose-dependently attenuates heat hypersensitivity in MrgprX1 mice. ML382 (lumbar puncture injection; 25 μM, 5 μL) leads to a significant increase in postconditioning time spent in the ML382-paired chamber, compared with the preconditioning value. ML382 inhibits nerve injury-induced ongoing pain in MrgprX1 mice^[1].