title: Binding of serotonin and N1-benzenesulfonyltryptamine-related analogs at human 5-HT6 serotonin receptors: receptor modeling studies.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0540, USA.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Dukat
authors.forename: Philip D
authors.initials: PD
authors.lastname: Mosier
authors.forename: Renata
authors.initials: R
authors.lastname: Kolanos
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Richard A
authors.initials: RA
authors.lastname: Glennon
mesh_terms: D000465:Algorithms; D000818:Animals; D001557:Benzenesulfonates / Q000737:chemistry*; D002417:Cattle; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D011759:Pyrrolidines / Q000737:chemistry; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000235:genetics; D012243:Rhodopsin / Q000737:chemistry; D012701:Serotonin / Q000031:analogs & derivatives* / Q000737:chemistry*; D012702:Serotonin Antagonists / Q000737:chemistry; D017366:Serotonin Receptor Agonists / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000737:chemistry; D014363:Tryptamines / Q000737:chemistry*
chemical_list: D001557:Benzenesulfonates; D008024:Ligands; C419803:N1-benzenesulfonyl-5-methoxy-N,N-dimethyltryptamine; D011759:Pyrrolidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013764:Tetrahydronaphthalenes; D014363:Tryptamines; C097216:serotonin 6 receptor; D012701:Serotonin; D012243:Rhodopsin