Tricyclic dihydroquinazolinones as novel 5-HT2C selective and orally efficacious anti-obesity agents.

Abstract Agonists of the 5-HT 2C receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT 2B receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT 2C agonists with no detectable agonism of the 5-HT 2B receptor is described. Among these, compounds (+)- 2a and (+)- 3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing.