Synthesis and SAR of potent and selective tetrahydropyrazinoisoquinolinone 5-HT(2C) receptor agonists.

Abstract

The 5-HT2C receptor has been implicated as a critical regulator of appetite. Small molecule activation of the 5-HT2C receptor has been shown to affect food intake and regulate body weight gain in rodent models and more recently in human clinical trials. Therefore, 5-HT2C is a well validated target for anti-obesity therapy. The synthesis and structure-activity relationships of a series of novel tetrahydropyrazinoisoquinolinone 5-HT2C receptor agonists are presented. Several members of this series were identified as potent 5-HT2C receptor agonists with high functional selectivity against the 5-HT2A and 5-HT2B receptors and reduced food intake in an acute rat feeding model upon oral dosing.

• Authors: Guohua Zhao, Chet Kwon, Sharon N Bisaha, Philip D Stein, Karen A Rossi, Xueying Cao, Thao Ung, Ginger Wu, Chen-Pin Hung, Sarah E Malmstrom, Ge Zhang, Qinling Qu, Jinping Gan, William J Keim, Mary Jane Cullen, Kenneth W Rohrbach, James Devenny, Mary Ann Pelleymounter, Keith J Miller, Jeffrey A Robl
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 23 Issue 13 Pg. 3914-9 (Jul 01 2013) ISSN: 1464-3405 [Electronic] England
• PMID: 23683593 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Isoquinolines
• Pyrazines
• Receptor, Serotonin, 5-HT2C

Topics

• Animals
• Crystallography, X-Ray
• Dose-Response Relationship, Drug
• Eating (drug effects)
• Humans
• Isoquinolines (chemical synthesis, chemistry, pharmacology)
• Models, Molecular
• Molecular Structure
• Pyrazines (chemical synthesis, chemistry, pharmacology)
• Rats
• Receptor, Serotonin, 5-HT2C (metabolism)
• Structure-Activity Relationship