Fig. 3: Molecular Interactions and Mechanisms of Phenethylamines.

A, B Showcases the binding mode and modeled electrostatic interactions of mescaline (A) and the novel arrestin-biased compound RS130-180 (B). C Top panel shows the vdW sphere of mescaline and L229^45.52/F234^5.38. The bottom two panels indicate the TRUPATH assays and site-directed mutagenesis for each residue. Each point represents the mean ± SEM and N = 3 biological replicates. It is of note that the negative curve-fit shown in this panel is for visualization purposes of the inverse agonism only – no fit parameters were obtained from this fit. D Chemical representation of RS130-180. The top right panel represents the overlay of the 5-HT structure (blue), RS130-180 (pink), and an inactive state structure (gray, PDB ID: 6A93) as shown via cartoon representation. The dose-response curve for Gq (TRUPATH) and arrestin for RS130-180 showcases the arrestin bias of the compound. Each point represents the mean ± SEM and N = 3 biological replicates and is taken from the raw data in Supplementary Fig. 13 and Supplementary Table 8. The bottom portion is close-up panels showcasing the structural mechanism that RS130-180 utilizes to achieve its arrestin bias.