Discovery of ß-Arrestin-Biased 25CN-NBOH-Derived 5-HT2A Receptor Agonists

The serotonin 2A receptor (5-HT2AR) is the mediator of the psychedelic effects of serotonergic psychedelics, which have shown promising results in clinical studies for several neuropsychiatric indications. The 5-HT2AR is able to signal through the G alpha(q) and ss-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-HT2AR 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(3x36). The lack of interaction between this hydroxyl moiety and Ser159(3x36) resulted in detrimental effects on potency and efficacy in both ss arr2 and miniGaq recruitment assays. Remarkably, G alpha(q)-mediated signaling was considerably more affected. This led to the development of the first efficacious ss arr2-biased 5-HT2AR agonists 4a-b and 6e-f, ss arr2 preferring, relative to lysergic acid diethylamide (LSD).