Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK─2100 Copenhagen, Denmark.
Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Campus Heymans, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
J Med Chem. 2022 Sep 22;65(18):12031-12043. doi: 10.1021/acs.jmedchem.2c00702. Epub 2022 Sep 13.
The serotonin 2A receptor (5-HTR) is the mediator of the psychedelic effects of serotonergic psychedelics, which have shown promising results in clinical studies for several neuropsychiatric indications. The 5-HTR is able to signal through the Gα 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-HTR 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. The lack of interaction between this hydroxyl moiety and Ser159 resulted in detrimental effects on potency and efficacy in both βarr2 and miniGα recruitment assays. Remarkably, Gα-mediated signaling was considerably more affected. This led to the development of the first efficacious βarr2-biased 5-HTR agonists and , βarr2 preferring, relative to lysergic acid diethylamide (LSD).
5-羟色胺 2A 受体（5-HTR）是血清素能致幻剂致幻作用的介质，这些致幻剂在几种神经精神疾病的临床研究中显示出了有希望的结果。5-HTR 能够通过 Gα 和β-arrestin 效应蛋白进行信号传递，但目前尚不清楚不同的信号通路如何为血清素能致幻剂介导的治疗效果做出贡献。在本工作中，我们评估了 5-HTR 亚型选择性激动剂 25CN-NBOH 及其一系列密切类似物在该受体上的偏置信号转导。这些配体旨在评估与 Ser159 相互作用的作用。缺乏该羟基与 Ser159 之间的相互作用导致在βarr2 和 miniGα招募测定中效力和功效都受到不利影响。值得注意的是，Gα 介导的信号转导受到的影响更大。这导致了第一个有效的βarr2 偏向性 5-HTR 激动剂的开发 和 ，与麦角酸二乙酰胺（LSD）相比，βarr2 更倾向于它们。
