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J Med Chem. 2008 Feb 14;51(3):603-11. doi: 10.1021/jm070910s. Epub 2008 Jan 18.

Binding of serotonin and N1-benzenesulfonyltryptamine-related analogs at human 5-HT6 serotonin receptors: receptor modeling studies.

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Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0540, USA.


A population of 100 graphics models of the human 5-HT6 serotonin receptor was constructed based on the structure of bovine rhodopsin. The endogenous tryptamine-based agonist serotonin (5-HT; 1) and the benzenesulfonyl-containing tryptamine-derived 5-HT6 receptor antagonist MS-245 (4a) were automatically docked with each of the 100 receptor models using a genetic algorithm approach. Similar studies were conducted with the more selective 5-HT6 receptor agonist EMDT (5) and optical isomers of EMDT-related analog 8, as well as with optical isomers of MS-245 (4a)-related and benzenesulfonyl-containing pyrrolidine 6 and aminotetralin 7. Although associated with the same general aromatic/hydrophobic binding cluster, 5-HT (1) and MS-245 (4a) were found to preferentially bind with distinct receptor conformations, and did so with different binding orientations (i.e., poses). A 5-HT pose/model was found to be common to EMDT (5) and its analogs, whereas that identified for MS-245 (4a) was found common to benzenesulfonyl-containing compounds. Specific amino acid residues were identified that can participate in binding, and evaluation of a sulfenamide analog of MS-245 indicates for the first time that the presence of the sulfonyl oxygen atoms enhances receptor affinity. The results indicate that the presence or absence of an N1-benzenesulfonyl group is a major determinant of the manner in which tryptamine-related agents bind at 5-HT6 serotonin receptors.

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