Antiobesity-like effects of the 5-HT2C receptor agonist WAY-161503.

Abstract WAY-161503 ((4a R )-8,9-dichloro-2,3,4,4a-tetrahydro-1 H -pyrazino[1,2-a]quinoxalin-5(6 H )-one), a 5-HT 2B/C receptor agonist, was characterized in vitro using stable Chinese hamster ovary cell lines expressing each of the human 5-HT 2 receptors and in vivo in animal models of obesity. WAY-161503 displaced both agonist ([ 125 I]2,5-dimethoxy-4-iodoamphetamine (DOI)) and antagonist ([ 3 H]mesulergine) radioligand binding to the human 5-HT 2C receptor with derived Ki values of 3.3 ± 0.9 and 32 ± 6 nM, respectively. Relative to 5-HT 2C receptor binding, WAY-161503 was approximately 6-fold less potent at human 5-HT 2A receptors ([ 125 I]DOI) with a derived Ki value of 18 nM and 20-fold less potent at human 5-HT 2B receptors ([ 3 H]5-HT) with a derived Ki value of 60 nM. In functional studies, WAY-161503 was a full agonist in stimulating 5-HT 2C -receptor-coupled [ 3 H]inositol phosphate (IP) formation and calcium mobilization with EC 50 values of 8.5 nM and 0.8 nM, respectively. WAY-161503 was also a 5-HT 2B agonist (EC 50 s of 6.9 and 1.8 nM for IP and calcium, respectively). In IP studies, WAY-161503 was a weak 5-HT 2A partial agonist (EC 50 , 802 nM) yet potently stimulated calcium mobilization (EC 50 , 7 nM) in 5-HT 2A receptor-expressing cells. Functionally, WAY-161503 also stimulated the phospholipase A 2 -coupled arachidonic acid release in 5-HT 2C receptor expressing cells albeit with lower potency (EC 50 , 38 nM) and efficacy (Emax, 77%) compared with activation of the PLC pathway. In vivo, WAY-161503 produced dose-dependent decreases in 2-h food intake in 24 h fasted normal Sprague–Dawley rats, diet-induced obese mice, and obese Zuker rats with ED 50 values of 1.9 mg/kg, 6.8 mg/kg, and 0.73 mg/kg, respectively. The reduction in food intake in normal Sprague–Dawley rats was reversed by administration of the 5-HT 2C receptor antagonist SB-242084. Following chronic administration (10 days) in growing Sprague–Dawley rats, WAY-161503 decreased food intake and attenuated body weight gain. Finally, following chronic administration (15 days) of WAY-161503 to obese Zuker rats, the rats maintained a 30% decrease in food intake over the 15-day period combined with a 25 g decrease in body weight relative to vehicle-treated controls demonstrating a lack of tolerance to its anorectic effects.