biostudies-literaturePoulie CBMH2020 Marie Sklodowska-Curie ActionsLundbeckfondenLundbeck FoundationNovo Nordisk Fonden12031-12043https://www.ebi.ac.uk/biostudies/studies/S-EPMC9511481biostudies-literatureUnknown65(18)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<sup>3×36</sJournal of medicinal chemistryDiscovery of β-Arrestin-Biased 25CN-NBOH-Derived 5-HT_2A Receptor Agonists.PMC9511481NNF18OC0031226R313-2019-526765657Harpsoe KPoulie CBMD'Andrea LPottie EKomarov IVStove CPSimon IAJensen AAKristensen JLGloriam DEfalseDiscovery 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<sup>3×36</s2022-01-01T00:00:00Z2022 Sep2025-07-25T03:08:08.519Z2025-04-05T17:54:46.998ZS-EPMC95114813609941110.1021/acs.jmedchem.2c00702