ABSTRACT
Obesity is one of the most serious public health problems worldwide in the 21st century. Current therapeutic treatment for obesity is mostly focused on preventive measures involving dietary control and physical exercises in combination with anti-obesity medications. However, most of these anti-obesity medications have little or no effect on weight loss, and some cases have demonstrated fatal side effects. Due to the urgent need for highly potent and selective anti-obesity agents, the serotonin receptors (5-HTR) have been the focus of much interest as a novel therapeutic target. In this report, we have developed pyrimidoazepine analogs targeting the 5-HT2A and 5-HT2C receptors and evaluated their biological activity in vitro and in vivo as novel anti-obesity agents. We were able to identify 6p as the most potent 5-HT2A and 5-HT2C ligand in vitro (IC50 = 3 nM and 2.3 nM, respectively), and this compound also demonstrated the greatest potency in vivo. In an acute obesity model, mice treated with 6p showed significant decrease in body weight gain and food intake over approximately 77-94% compared to a control group. In a chronic obesity model, mice treated with 6p also showed a marked decrease in food intake and body weight gain.
Subject(s)
Anti-Obesity Agents/pharmacology , Obesity/prevention & control , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin Agents/pharmacology , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacokinetics , Area Under Curve , Azepines/chemistry , Azepines/pharmacokinetics , Azepines/pharmacology , Binding, Competitive , Dose-Response Relationship, Drug , Eating/drug effects , HEK293 Cells , Humans , Ligands , Male , Metabolic Clearance Rate , Mice , Mice, Inbred C57BL , Mice, Obese , Models, Chemical , Molecular Structure , Obesity/metabolism , Pyrimidines/chemistry , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT2A/genetics , Receptor, Serotonin, 5-HT2C/genetics , Serotonin Agents/chemical synthesis , Serotonin Agents/pharmacokinetics , Weight Gain/drug effectsABSTRACT
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.
