Discovery of β-Arrestin-Biased 25CN-NBOH-Derived 5-HT2A Receptor Agonists

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Discovery of β-Arrestin-Biased 25CN-NBOH-Derived 5-HT2A Receptor Agonists. / Poulie, Christian B M; Pottie, Eline; Simon, Icaro A; Harpsøe, Kasper; D'Andrea, Laura; Komarov, Igor V; Gloriam, David E; Jensen, Anders A; Stove, Christophe P; Kristensen, Jesper L.

In: Journal of Medicinal Chemistry, Vol. 65, No. 18, 2022, p. 12031–12043.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Poulie, CBM, Pottie, E, Simon, IA, Harpsøe, K, D'Andrea, L, Komarov, IV, Gloriam, DE, Jensen, AA, Stove, CP & Kristensen, JL 2022, 'Discovery of β-Arrestin-Biased 25CN-NBOH-Derived 5-HT2A Receptor Agonists', Journal of Medicinal Chemistry, vol. 65, no. 18, pp. 12031–12043. https://doi.org/10.1021/acs.jmedchem.2c00702

APA

Poulie, C. B. M., Pottie, E., Simon, I. A., Harpsøe, K., D'Andrea, L., Komarov, I. V., Gloriam, D. E., Jensen, A. A., Stove, C. P., & Kristensen, J. L. (2022). Discovery of β-Arrestin-Biased 25CN-NBOH-Derived 5-HT2A Receptor Agonists. Journal of Medicinal Chemistry, 65(18), 12031–12043. https://doi.org/10.1021/acs.jmedchem.2c00702

Vancouver

Poulie CBM, Pottie E, Simon IA, Harpsøe K, D'Andrea L, Komarov IV et al. Discovery of β-Arrestin-Biased 25CN-NBOH-Derived 5-HT2A Receptor Agonists. Journal of Medicinal Chemistry. 2022;65(18):12031–12043. https://doi.org/10.1021/acs.jmedchem.2c00702

Author

Poulie, Christian B M ; Pottie, Eline ; Simon, Icaro A ; Harpsøe, Kasper ; D'Andrea, Laura ; Komarov, Igor V ; Gloriam, David E ; Jensen, Anders A ; Stove, Christophe P ; Kristensen, Jesper L. / Discovery of β-Arrestin-Biased 25CN-NBOH-Derived 5-HT2A Receptor Agonists. In: Journal of Medicinal Chemistry. 2022 ; Vol. 65, No. 18. pp. 12031–12043.

Bibtex

@article{89abd6c9fc5a41788a1495a593ce8101,
title = "Discovery of β-Arrestin-Biased 25CN-NBOH-Derived 5-HT2A Receptor Agonists",
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).",
keywords = "Hallucinogens/pharmacology, Lysergic Acid Diethylamide/pharmacology, Receptor, Serotonin, 5-HT2A, Serotonin, Serotonin 5-HT2 Receptor Agonists/pharmacology, beta-Arrestins",
author = "Poulie, {Christian B M} and Eline Pottie and Simon, {Icaro A} and Kasper Harps{\o}e and Laura D'Andrea and Komarov, {Igor V} and Gloriam, {David E} and Jensen, {Anders A} and Stove, {Christophe P} and Kristensen, {Jesper L}",
year = "2022",
doi = "10.1021/acs.jmedchem.2c00702",
language = "English",
volume = "65",
pages = "12031–12043",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "18",

}

RIS

TY - JOUR

T1 - Discovery of β-Arrestin-Biased 25CN-NBOH-Derived 5-HT2A Receptor Agonists

AU - Poulie, Christian B M

AU - Pottie, Eline

AU - Simon, Icaro A

AU - Harpsøe, Kasper

AU - D'Andrea, Laura

AU - Komarov, Igor V

AU - Gloriam, David E

AU - Jensen, Anders A

AU - Stove, Christophe P

AU - Kristensen, Jesper L

PY - 2022

Y1 - 2022

N2 - 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).

AB - 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).

KW - Hallucinogens/pharmacology

KW - Lysergic Acid Diethylamide/pharmacology

KW - Receptor, Serotonin, 5-HT2A

KW - Serotonin

KW - Serotonin 5-HT2 Receptor Agonists/pharmacology

KW - beta-Arrestins

U2 - 10.1021/acs.jmedchem.2c00702

DO - 10.1021/acs.jmedchem.2c00702

M3 - Journal article

C2 - 36099411

VL - 65

SP - 12031

EP - 12043

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 18

ER -

ID: 319364800