Discovery of β-Arrestin-Biased 25CN-NBOH-Derived 5-HT_2A Receptor Agonists

The serotonin 2A receptor (5-HT_2AR) is the mediator of the psychedelic effects of serotonergic psychedelics, which have shown promising results in clinical studies for several neuropsychiatric indications. The 5-HT_2AR is able to signal through the Gα_q and β-arrestin effector proteins, but it is currently not known how the different signaling pathways contribute to the therapeutic effects mediated by serotonergic psychedelics. In the present work, we have evaluated the subtype-selective 5-HT_2AR agonist 25CN-NBOH and a series of close analogues for biased signaling at this receptor. These ligands were designed to evaluate the role of interactions with Ser159^3×36. The lack of interaction between this hydroxyl moiety and Ser159^3×36 resulted in detrimental effects on potency and efficacy in both βarr2 and miniGα_q recruitment assays. Remarkably, Gα_q-mediated signaling was considerably more affected. This led to the development of the first efficacious βarr2-biased 5-HT_2AR agonists 4a-b and 6e-f, βarr2 preferring, relative to lysergic acid diethylamide (LSD).