Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-ht2 receptors

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Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-ht2 receptors. / Isberg, Vignir; Paine, James; Leth-Petersen, Sebastian; Kristensen, Jesper Langgaard; Gloriam, David E.

In: P L o S One, Vol. 8, No. 11, e78515, 2013.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Isberg, V, Paine, J, Leth-Petersen, S, Kristensen, JL & Gloriam, DE 2013, 'Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-ht2 receptors', P L o S One, vol. 8, no. 11, e78515. https://doi.org/10.1371/journal.pone.0078515

APA

Isberg, V., Paine, J., Leth-Petersen, S., Kristensen, J. L., & Gloriam, D. E. (2013). Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-ht2 receptors. P L o S One, 8(11), [e78515]. https://doi.org/10.1371/journal.pone.0078515

Vancouver

Isberg V, Paine J, Leth-Petersen S, Kristensen JL, Gloriam DE. Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-ht2 receptors. P L o S One. 2013;8(11). e78515. https://doi.org/10.1371/journal.pone.0078515

Author

Isberg, Vignir ; Paine, James ; Leth-Petersen, Sebastian ; Kristensen, Jesper Langgaard ; Gloriam, David E. / Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-ht2 receptors. In: P L o S One. 2013 ; Vol. 8, No. 11.

Bibtex

@article{cbe01d2881e542ecaae77da2e1777d2f,
title = "Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-ht2 receptors",
abstract = "Serotonergic ligands have proven effective drugs in the treatment of migraine, pain, obesity, and a wide range of psychiatric and neurological disorders. There is a clinical need for more highly 5-HT2 receptor subtype-selective ligands and the most attention has been given to the phenethylamine class. Conformationally constrained phenethylamine analogs have demonstrated that for optimal activity the free lone pair electrons of the 2-oxygen must be oriented syn and the 5-oxygen lone pairs anti relative to the ethylamine moiety. Also the ethyl linker has been constrained providing information about the bioactive conformation of the amine functionality. However, combined 1,2-constriction by cyclization has only been tested with one compound. Here, we present three new 1,2-cyclized phenylethylamines, 9-11, and describe their synthetic routes. Ligand docking in the 5-HT2B crystal structure showed that the 1,2-heterocyclized compounds can be accommodated in the binding site. Conformational analysis showed that 11 can only bind in a higher-energy conformation, which would explain its absent or low affinity. The amine and 2-oxygen interactions with D3.32 and S3.36, respectively, can form but shift the placement of the core scaffold. The constraints in 9-11 resulted in docking poses with the 4-bromine in closer vicinity to 5.46, which is polar only in the human 5-HT2A subtype, for which 9-11 have the lowest affinity. The new ligands, conformational analysis and docking expand the structure-activity relationships of constrained phenethylamines and contributes towards the development of 5-HT2 receptor subtype-selective ligands.",
author = "Vignir Isberg and James Paine and Sebastian Leth-Petersen and Kristensen, {Jesper Langgaard} and Gloriam, {David E}",
year = "2013",
doi = "10.1371/journal.pone.0078515",
language = "English",
volume = "8",
journal = "P L o S One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "11",

}

RIS

TY - JOUR

T1 - Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-ht2 receptors

AU - Isberg, Vignir

AU - Paine, James

AU - Leth-Petersen, Sebastian

AU - Kristensen, Jesper Langgaard

AU - Gloriam, David E

PY - 2013

Y1 - 2013

N2 - Serotonergic ligands have proven effective drugs in the treatment of migraine, pain, obesity, and a wide range of psychiatric and neurological disorders. There is a clinical need for more highly 5-HT2 receptor subtype-selective ligands and the most attention has been given to the phenethylamine class. Conformationally constrained phenethylamine analogs have demonstrated that for optimal activity the free lone pair electrons of the 2-oxygen must be oriented syn and the 5-oxygen lone pairs anti relative to the ethylamine moiety. Also the ethyl linker has been constrained providing information about the bioactive conformation of the amine functionality. However, combined 1,2-constriction by cyclization has only been tested with one compound. Here, we present three new 1,2-cyclized phenylethylamines, 9-11, and describe their synthetic routes. Ligand docking in the 5-HT2B crystal structure showed that the 1,2-heterocyclized compounds can be accommodated in the binding site. Conformational analysis showed that 11 can only bind in a higher-energy conformation, which would explain its absent or low affinity. The amine and 2-oxygen interactions with D3.32 and S3.36, respectively, can form but shift the placement of the core scaffold. The constraints in 9-11 resulted in docking poses with the 4-bromine in closer vicinity to 5.46, which is polar only in the human 5-HT2A subtype, for which 9-11 have the lowest affinity. The new ligands, conformational analysis and docking expand the structure-activity relationships of constrained phenethylamines and contributes towards the development of 5-HT2 receptor subtype-selective ligands.

AB - Serotonergic ligands have proven effective drugs in the treatment of migraine, pain, obesity, and a wide range of psychiatric and neurological disorders. There is a clinical need for more highly 5-HT2 receptor subtype-selective ligands and the most attention has been given to the phenethylamine class. Conformationally constrained phenethylamine analogs have demonstrated that for optimal activity the free lone pair electrons of the 2-oxygen must be oriented syn and the 5-oxygen lone pairs anti relative to the ethylamine moiety. Also the ethyl linker has been constrained providing information about the bioactive conformation of the amine functionality. However, combined 1,2-constriction by cyclization has only been tested with one compound. Here, we present three new 1,2-cyclized phenylethylamines, 9-11, and describe their synthetic routes. Ligand docking in the 5-HT2B crystal structure showed that the 1,2-heterocyclized compounds can be accommodated in the binding site. Conformational analysis showed that 11 can only bind in a higher-energy conformation, which would explain its absent or low affinity. The amine and 2-oxygen interactions with D3.32 and S3.36, respectively, can form but shift the placement of the core scaffold. The constraints in 9-11 resulted in docking poses with the 4-bromine in closer vicinity to 5.46, which is polar only in the human 5-HT2A subtype, for which 9-11 have the lowest affinity. The new ligands, conformational analysis and docking expand the structure-activity relationships of constrained phenethylamines and contributes towards the development of 5-HT2 receptor subtype-selective ligands.

U2 - 10.1371/journal.pone.0078515

DO - 10.1371/journal.pone.0078515

M3 - Journal article

VL - 8

JO - P L o S One

JF - P L o S One

SN - 1932-6203

IS - 11

M1 - e78515

ER -

ID: 75746283