Discovery of β-Arrestin-Biased 25CN-NBOH-Derived 5-HT2A Receptor Agonists.
Christian B M Poulie, Eline Pottie, Icaro A Simon, Kasper Harpsøe, Laura D'Andrea, Igor V Komarov, David E Gloriam, Anders A Jensen, Christophe P Stove, Jesper L Kristensen
Journal of medicinal chemistry September 22, 2022 DOI: 10.1021/acs.jmedchem.2c00702 via PubMed
Summary
AI-generated from the abstractThe serotonin 2A receptor (5-HT2AR) is responsible for the psychedelic effects of certain drugs, which show promise for treating neuropsychiatric conditions. This work examined how a series of compounds, including 25CN-NBOH, signal through two pathways: Gαq and β-arrestin. Disrupting the interaction with a specific amino acid, Ser1593×36, reduced both pathways' potency and efficacy, with Gαq signaling more strongly affected. This led to the creation of the first effective β-arrestin-biased 5-HT2AR agonists (4a-b and 6e-f), which prefer the β-arrestin pathway over Gαq relative to LSD.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Intervention | 6e-f |
| Keywords | Neuroscience Psychedelic-medicine Pharmacology Mental-health Serotonin-research |
| Citations | 32 |
| Key finding | Disrupting the interaction with Ser1593×36 reduced Gαq signaling more than β-arrestin signaling, enabling the development of β-arrestin-biased 5-HT2AR agonists 4a-b and 6e-f. |
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).