Fig. 3 |. Structure–activity relationships of AS408 analogs.

Dose–response curves indicate a negative allosteric effect of AS408 analogs on norepinephrine-stimulated β-arrestin recruitment. Modulators were tested at concentrations of 10 μM (blue) and 30 μM (yellow) compared to norepinephrine alone (purple). Data are derived from 2–12 experiments each done in duplicate and given as mean ± s.e.m. if n ≥ 3, or as mean if n = 2; the sample size (n) is labeled in the figure. Highlighted in bold is the structure of the bromo substituted phenyl ring of AS408. The receptor–ligand models show crucial parts of the crystal structure and the respective modulator aligned with the coordinates of AS408 visualizing the impact of structural modifications on receptor–ligand interactions. Red circles indicate repulsive interactions, the green circle indicates the missing polar interaction network.