Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-HT2 receptors.
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 clas...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3820707?pdf=render |
| _version_ | 1818840959964676096 |
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| author | Vignir Isberg James Paine Sebastian Leth-Petersen Jesper L Kristensen David E Gloriam |
| author_facet | Vignir Isberg James Paine Sebastian Leth-Petersen Jesper L Kristensen David E Gloriam |
| author_sort | Vignir Isberg |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T04:18:29Z |
| format | Article |
| id | doaj.art-22e6dc693405453cbae88913e5682d3d |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-19T04:18:29Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-22e6dc693405453cbae88913e5682d3d2022-12-21T20:36:13ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-01811e7851510.1371/journal.pone.0078515Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-HT2 receptors.Vignir IsbergJames PaineSebastian Leth-PetersenJesper L KristensenDavid E GloriamSerotonergic 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.http://europepmc.org/articles/PMC3820707?pdf=render |
| spellingShingle | Vignir Isberg James Paine Sebastian Leth-Petersen Jesper L Kristensen David E Gloriam Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-HT2 receptors. PLoS ONE |
| title | Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-HT2 receptors. |
| title_full | Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-HT2 receptors. |
| title_fullStr | Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-HT2 receptors. |
| title_full_unstemmed | Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-HT2 receptors. |
| title_short | Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-HT2 receptors. |
| title_sort | structure activity relationships of constrained phenylethylamine ligands for the serotonin 5 ht2 receptors |
| url | http://europepmc.org/articles/PMC3820707?pdf=render |
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