Discovery of β-Arrestin-Biased 25CN-NBOH-Derived 5-HT(2A) Receptor Agonists

[Image: see text] The serotonin 2A receptor (5-HT(2A)R) 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(2A)R 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(2A)R 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(2A)R agonists 4a–b and 6e–f, βarr2 preferring, relative to lysergic acid diethylamide (LSD).