Synthesis and SAR of potent and selective tetrahydropyrazinoisoquinolinone 5-HT2C receptor agonists

Abstract The 5-HT 2C receptor has been implicated as a critical regulator of appetite. Small molecule activation of the 5-HT 2C 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-HT 2C is a well validated target for anti-obesity therapy. The synthesis and structure–activity relationships of a series of novel tetrahydropyrazinoisoquinolinone 5-HT 2C receptor agonists are presented. Several members of this series were identified as potent 5-HT 2C receptor agonists with high functional selectivityagainst the 5-HT 2A and 5-HT 2B receptors and reduced food intake in an acute rat feeding model upon oral dosing.