@article{7ba76e76fd034d5985b8606b135c74a6,
title = "Photoswitchable Serotonins for Optical Control of the 5-HT2A Receptor**",
abstract = "Serotonin receptors play central roles in neuromodulation and are critical drug targets for psychiatric disorders. Optical control of serotonin receptor subtypes has the potential to greatly enhance our understanding of the spatiotemporal dynamics of receptor function. While other neuromodulatory receptors have been successfully rendered photoswitchable, reversible photocontrol of serotonin receptors has not been achieved, representing a major gap in GPCR photopharmacology. Herein, we develop the first tools that allow for such control. Azo5HT-2 shows light-dependent 5-HT2AR agonism, with greater activity in the cis-form. Based on docking and test compound analysis, we also develop photoswitchable orthogonal, remotely-tethered ligands (PORTLs). These BG-Azo5HTs provide rapid, reversible, and repeatable optical control following conjugation to SNAP-tagged 5-HT2AR. Overall, this study provides a foundation for the broad extension of photopharmacology to the serotonin receptor family.",
keywords = "GPCR, Photopharmacology, Photoswitch, SNAP Tag, Serotonin",
author = "Johannes Morstein and Giovanna Romano and Hetzler, {Belinda E.} and Ambrose Plante and Caleb Haake and Joshua Levitz and Dirk Trauner",
note = "Funding Information: We thank New York University for financial support. We thank Jordana Thibado for preliminary functional studies and SNAP‐5HTR cloning. NMR spectra were acquired using the TCI cryoprobe supported by the NIH (OD016343). J.M. thanks the New York University for a Margaret and Herman Sokol fellowship, and the NCI for a K00 award (4K00CA253758). G.R. is supported by the Weill Cornell Molecular Biophysics Training Grant (T32GM132081). A.P. gratefully acknowledges support from NSF grant BIGDATA: IA: Collaborative Research: In situ Data Analytics for Next Generation Molecular Dynamics Workflows (NSF #1740990) and computational resources from (project BIP109) of the Oak Ridge Leadership Computing Facility under Contract DE‐AC05‐00OR22725. J.L. and D.T. are supported by an R61 (R61 DA051529) grant from NIDA. J.L. is supported by an R35 grant (R35GM124731) from NIGMS, the Rohr Family Research Scholar Award and the Irma T. Hirschl/Monique Weill‐Caulier Research Award. D.T. thanks the McKnight Foundation for a McKnight Memory and Cognitive Disorders Award. 2A Funding Information: We thank New York University for financial support. We thank Jordana Thibado for preliminary functional studies and SNAP-5HT2AR cloning. NMR spectra were acquired using the TCI cryoprobe supported by the NIH (OD016343). J.M. thanks the New York University for a Margaret and Herman Sokol fellowship, and the NCI for a K00 award (4K00CA253758). G.R. is supported by the Weill Cornell Molecular Biophysics Training Grant (T32GM132081). A.P. gratefully acknowledges support from NSF grant BIGDATA: IA: Collaborative Research: In situ Data Analytics for Next Generation Molecular Dynamics Workflows (NSF #1740990) and computational resources from (project BIP109) of the Oak Ridge Leadership Computing Facility under Contract DE-AC05-00OR22725. J.L. and D.T. are supported by an R61 (R61 DA051529) grant from NIDA. J.L. is supported by an R35 grant (R35GM124731) from NIGMS, the Rohr Family Research Scholar Award and the Irma T. Hirschl/Monique Weill-Caulier Research Award. D.T. thanks the McKnight Foundation for a McKnight Memory and Cognitive Disorders Award. Publisher Copyright: {\textcopyright} 2022 Wiley-VCH GmbH.",
year = "2022",
month = apr,
day = "25",
doi = "10.1002/anie.202117094",
language = "English (US)",
volume = "61",
journal = "Angewandte Chemie - International Edition",
issn = "1433-7851",
publisher = "John Wiley and Sons Ltd",
number = "18",
}