title: 5-HT₂c receptor selectivity and structure-activity relationship of N-methyl-N-(1-methylpiperidin-4-yl)benzenesulfonamide analogs.
abstract: Agonists of the 5-HT(2C) receptor have attracted much attention as therapeutic agents for the treatment of obesity. Subtype selectivity against other 5-HT(2) receptors is one of the most important prerequisites for reducing side effects. We present the synthesis of N-methyl-N-(1-methylpiperidin-4-yl)benzenesulfonamide analogs and their structure-activity relationship studies on 5-HT(2A) and 5-HT(2C) receptors. Although the compounds showed nanomolar activity to the 5-HT(2C) receptor, their selectivity against the 5-HT(2A) receptor was modest to low. Molecular modeling studies using homology modeling and docking simulation revealed that selectivity originated from subtype specific residues. The observed binding modes and receptor-ligand interactions provided us a clue for optimizing the selectivity against the 5-HT(2A) receptor.
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea.
authors.forename: Jae Wan
authors.initials: JW
authors.lastname: Jang
authors.forename: Je-Sook
authors.initials: JS
authors.lastname: Baek
authors.forename: Gil Don
authors.initials: GD
authors.lastname: Choi
authors.forename: Woo-Kyu
authors.initials: WK
authors.lastname: Park
authors.forename: Yong Seo
authors.initials: YS
authors.lastname: Cho
authors.forename: Du-Jong
authors.initials: DJ
authors.lastname: Baek
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
mesh_terms: D000595:Amino Acid Sequence; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding; D044405:Receptor, Serotonin, 5-HT2C / Q000737:chemistry* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012701:Serotonin / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D008024:Ligands; D010880:Piperidines; D044405:Receptor, Serotonin, 5-HT2C; D012701:Serotonin; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C573850:N-methyl-N-(1-methylpiperidin-4-yl)benzenesulfonamide