Faculty Collaboration Database

Binding of serotonin and N1-benzenesulfonyltryptamine-related analogs at human 5-HT6 serotonin receptors: receptor modeling studies. J Med Chem 2008 Feb 14;51(3):603-11

Date

01/19/2008

Pubmed ID

18201064

Pubmed Central ID

PMC5994921

DOI

10.1021/jm070910s

Scopus ID

2-s2.0-39149119649 (requires institutional sign-in at Scopus site)   35 Citations

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.

Author List

Dukat M, Mosier PD, Kolanos R, Roth BL, Glennon RA

Author

Philip Mosier PhD Assistant Professor in the School of Pharmacy Administration department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Algorithms
Animals
Benzenesulfonates
Cattle
Humans
Hydrophobic and Hydrophilic Interactions
Ligands
Models, Molecular
Mutagenesis, Site-Directed
Protein Conformation
Pyrrolidines
Receptors, Serotonin
Rhodopsin
Serotonin
Serotonin Antagonists
Serotonin Receptor Agonists
Stereoisomerism
Structure-Activity Relationship
Tetrahydronaphthalenes
Tryptamines