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. Author manuscript; available in PMC: 2022 Jun 1.
Published in final edited form as: Nature. 2021 Nov 17;600(7887):170–175. doi: 10.1038/s41586-021-04126-6

Fig. 3 |. Discovery of MRGPRX2 selective inverse agonists.

Fig. 3 |

a, Overview of the analog optimization toward compound C9 and C9-6. b, C9 and C9-6 show improved antagonist activity for MRGPRX2 when compared to the parent compound ‘1592. C7 is shown as an inactive control. EC80 (R)-ZINC-3573 concentration (3 μM) was added in the antagonist mode FLIPR Ca2+ assay. Data represent mean ± SEM of n = 3 biological replicates. c, Compound C9 and C9-6 inhibit the basal recruitment of Gq by MRGPRX2 and display inverse agonist activities. Data represent mean ± SEM of n = 3 biological replicates. d, C9 and C9-6 inhibit substance P (10 μM) stimulated MRGPRX2 activation. Data represent mean ± SEM of n = 3 biological replicates. e-f, C9 and C9-6 display no antagonist activity towards NK1R (e) and MRGPRX4 (f) in FLIPR assay. Agonist concentrations in the antagonist assay were shown in the graph title. C7 is used as a negative control. Data represent mean ± SEM of n = 3 biological replicates. g, Compound C9 inhibit MRGPRX2 mediated LAD2 human mast activation. Data represent mean ± SEM. Samples were run in quadruplicate with n=2 biological replicates.