Identification of 5-HT2 Serotonin Receptor Modulators through the Synthesis of a Diverse, Tropane- and Quinuclidine-alkaloid-Inspired Compound Library

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

Standard

Identification of 5-HT2 Serotonin Receptor Modulators through the Synthesis of a Diverse, Tropane- and Quinuclidine-alkaloid-Inspired Compound Library. / Yao, Ruwei; Jensen, Anders A; Bryce-Rogers, Hogan P; Schultz-Knudsen, Katrine; Zhou, Libin; Hovendal, Nicklas P; Pedersen, Henrik; Kubus, Mariusz; Ulven, Trond; Laraia, Luca.

In: Journal of Medicinal Chemistry, Vol. 66, No. 16, 2023, p. 11536-11554.

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

Harvard

Yao, R, Jensen, AA, Bryce-Rogers, HP, Schultz-Knudsen, K, Zhou, L, Hovendal, NP, Pedersen, H, Kubus, M, Ulven, T & Laraia, L 2023, 'Identification of 5-HT2 Serotonin Receptor Modulators through the Synthesis of a Diverse, Tropane- and Quinuclidine-alkaloid-Inspired Compound Library', Journal of Medicinal Chemistry, vol. 66, no. 16, pp. 11536-11554. https://doi.org/10.1021/acs.jmedchem.3c01059

APA

Yao, R., Jensen, A. A., Bryce-Rogers, H. P., Schultz-Knudsen, K., Zhou, L., Hovendal, N. P., Pedersen, H., Kubus, M., Ulven, T., & Laraia, L. (2023). Identification of 5-HT2 Serotonin Receptor Modulators through the Synthesis of a Diverse, Tropane- and Quinuclidine-alkaloid-Inspired Compound Library. Journal of Medicinal Chemistry, 66(16), 11536-11554. https://doi.org/10.1021/acs.jmedchem.3c01059

Vancouver

Yao R, Jensen AA, Bryce-Rogers HP, Schultz-Knudsen K, Zhou L, Hovendal NP et al. Identification of 5-HT2 Serotonin Receptor Modulators through the Synthesis of a Diverse, Tropane- and Quinuclidine-alkaloid-Inspired Compound Library. Journal of Medicinal Chemistry. 2023;66(16):11536-11554. https://doi.org/10.1021/acs.jmedchem.3c01059

Author

Yao, Ruwei ; Jensen, Anders A ; Bryce-Rogers, Hogan P ; Schultz-Knudsen, Katrine ; Zhou, Libin ; Hovendal, Nicklas P ; Pedersen, Henrik ; Kubus, Mariusz ; Ulven, Trond ; Laraia, Luca. / Identification of 5-HT2 Serotonin Receptor Modulators through the Synthesis of a Diverse, Tropane- and Quinuclidine-alkaloid-Inspired Compound Library. In: Journal of Medicinal Chemistry. 2023 ; Vol. 66, No. 16. pp. 11536-11554.

Bibtex

@article{47fbdddd7f0841fe94d655d2c89fbb25,
title = "Identification of 5-HT2 Serotonin Receptor Modulators through the Synthesis of a Diverse, Tropane- and Quinuclidine-alkaloid-Inspired Compound Library",
abstract = "The recombination of natural product (NP) fragments in unprecedented ways has emerged as an important strategy for bioactive compound discovery. In this context, we propose that privileged primary fragments predicted to be enriched in activity against a specific target class can be coupled to diverse secondary fragments to engineer selectivity among closely related targets. Here, we report the synthesis of an alkaloid-inspired compound library enriched in spirocyclic ring fusions, comprising 58 compounds from 12 tropane- or quinuclidine-containing scaffolds, all of which can be considered pseudo-NPs. The library displays excellent predicted drug-like properties including high Fsp3 content and Lipinski's rule-of-five compliance. Targeted screening against selected members of the serotonin and dopamine G protein-coupled receptor family led to the identification of several hits that displayed significant agonist or antagonist activity against 5-HT2A and/or 5-HT2C, and subsequent optimization of one of these delivered a lead dual 5-HT2B/C antagonist with a highly promising selectivity profile.",
keywords = "Alkaloids/pharmacology, Receptor, Serotonin, 5-HT2A, Receptor, Serotonin, 5-HT2C, Receptors, Serotonin, Serotonin, Serotonin 5-HT2 Receptor Agonists/pharmacology, Serotonin 5-HT2 Receptor Antagonists/pharmacology, Tropanes, Quinuclidines/chemistry",
author = "Ruwei Yao and Jensen, {Anders A} and Bryce-Rogers, {Hogan P} and Katrine Schultz-Knudsen and Libin Zhou and Hovendal, {Nicklas P} and Henrik Pedersen and Mariusz Kubus and Trond Ulven and Luca Laraia",
year = "2023",
doi = "10.1021/acs.jmedchem.3c01059",
language = "English",
volume = "66",
pages = "11536--11554",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "16",

}

RIS

TY - JOUR

T1 - Identification of 5-HT2 Serotonin Receptor Modulators through the Synthesis of a Diverse, Tropane- and Quinuclidine-alkaloid-Inspired Compound Library

AU - Yao, Ruwei

AU - Jensen, Anders A

AU - Bryce-Rogers, Hogan P

AU - Schultz-Knudsen, Katrine

AU - Zhou, Libin

AU - Hovendal, Nicklas P

AU - Pedersen, Henrik

AU - Kubus, Mariusz

AU - Ulven, Trond

AU - Laraia, Luca

PY - 2023

Y1 - 2023

N2 - The recombination of natural product (NP) fragments in unprecedented ways has emerged as an important strategy for bioactive compound discovery. In this context, we propose that privileged primary fragments predicted to be enriched in activity against a specific target class can be coupled to diverse secondary fragments to engineer selectivity among closely related targets. Here, we report the synthesis of an alkaloid-inspired compound library enriched in spirocyclic ring fusions, comprising 58 compounds from 12 tropane- or quinuclidine-containing scaffolds, all of which can be considered pseudo-NPs. The library displays excellent predicted drug-like properties including high Fsp3 content and Lipinski's rule-of-five compliance. Targeted screening against selected members of the serotonin and dopamine G protein-coupled receptor family led to the identification of several hits that displayed significant agonist or antagonist activity against 5-HT2A and/or 5-HT2C, and subsequent optimization of one of these delivered a lead dual 5-HT2B/C antagonist with a highly promising selectivity profile.

AB - The recombination of natural product (NP) fragments in unprecedented ways has emerged as an important strategy for bioactive compound discovery. In this context, we propose that privileged primary fragments predicted to be enriched in activity against a specific target class can be coupled to diverse secondary fragments to engineer selectivity among closely related targets. Here, we report the synthesis of an alkaloid-inspired compound library enriched in spirocyclic ring fusions, comprising 58 compounds from 12 tropane- or quinuclidine-containing scaffolds, all of which can be considered pseudo-NPs. The library displays excellent predicted drug-like properties including high Fsp3 content and Lipinski's rule-of-five compliance. Targeted screening against selected members of the serotonin and dopamine G protein-coupled receptor family led to the identification of several hits that displayed significant agonist or antagonist activity against 5-HT2A and/or 5-HT2C, and subsequent optimization of one of these delivered a lead dual 5-HT2B/C antagonist with a highly promising selectivity profile.

KW - Alkaloids/pharmacology

KW - Receptor, Serotonin, 5-HT2A

KW - Receptor, Serotonin, 5-HT2C

KW - Receptors, Serotonin

KW - Serotonin

KW - Serotonin 5-HT2 Receptor Agonists/pharmacology

KW - Serotonin 5-HT2 Receptor Antagonists/pharmacology

KW - Tropanes

KW - Quinuclidines/chemistry

U2 - 10.1021/acs.jmedchem.3c01059

DO - 10.1021/acs.jmedchem.3c01059

M3 - Journal article

C2 - 37566000

VL - 66

SP - 11536

EP - 11554

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 16

ER -

ID: 365597915