Open AccessStructure-Activity Relationships of Constrained Phenylethylamine Ligands for the Serotonin 5-HT2 Receptors
Author(s) -
Vignir Ísberg,
James S. Paine,
Sebastian LethPetersen,
Jesper L. Kristensen,
David E. Gloriam
Publication year - 2013
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0078515
Subject(s) - phenethylamine , chemistry , stereochemistry , phenethylamines , docking (animal) , g protein coupled receptor , allosteric regulation , moiety , serotonin , ligand (biochemistry) , receptor , biochemistry , medicine , nursing
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-HT 2 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-HT 2B 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-HT 2A 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-HT 2 receptor subtype-selective ligands.