Discovery of β-Arrestin-Biased 25CN-NBOH-Derived 5-HT2A Receptor Agonists.
Journal of medicinal chemistry – September 22, 2022
Source: PubMed
Summary
Scientists have discovered new compounds that interact with serotonin receptors in a unique way, offering potential insights into how psychedelic medicines work in the brain. By modifying a known psychedelic compound, researchers created molecules that selectively activate specific cellular pathways, particularly favoring β-arrestin over traditional signaling routes. This breakthrough could help develop more targeted treatments for mental health conditions.
Abstract
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 Gαq 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-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 Ser1593×36. The lack of interaction between this hydroxyl moiety and Ser1593×36 resulted in detrimental effects on potency and efficacy in both βarr2 and miniGαq recruitment assays. Remarkably, Gαq-mediated signaling was considerably more affected. This led to the development of the first efficacious βarr2-biased 5-HT2AR agonists 4a-b and 6e-f, βarr2 preferring, relative to lysergic acid diethylamide (LSD).