The serotonin 2A receptor (5-HT2AR) is the primary receptor through which the classical psychedelics exert their effects and have shown promising results in pilot studies on various neurotherapeutic indications.[1] The 5-HT2AR can signal through Gαq and β-arrestin 2 (βarr2) effector proteins, among others.[2] However, the exact roles of these various signaling pathways on the therapeutic effects of serotonergic psychedelics are not yet fully understood. 

In this work, we have made quantitative structure-activity relationship (QSAR) models, based on various physicochemical parameters of the well-known 2C-X class of psychedelic phenethylamines.[3] In an attempt to elucidate the intricate mechanisms underlying biased agonism at the 5-HT2AR, we constructed QSAR models for both the Gαq and βarr2 signaling pathways. Based on these QSAR models, dockings and molecular dynamics simulations were performed to elucidate the binding modes of the 2C-X agonists, providing further insights into the structural basis of signaling pathway selectivity. These insights led us to the design and synthesis of a small series of novel 5-HT2AR agonists, which were evaluated for biased signaling via bioassays measuring the recruitment of either βarr2 and miniGαq in the wild-type 5-HT2AR[4], as well as in selected 5-HT2AR mutants. Thus, this work provides key understandings of the ligand-receptor interactions associated with biased signaling.