Antiobesity-like effects of the 5-HT2C receptor agonist WAY-161503.
WAY-161503 ((4aR)-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-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-HT2 receptors and in vivo in animal models of obesity. WAY-161503 displaced both agonist ([125I]2,5-dimethoxy-4-iodoamphetamine (DOI)) and antagonist ([3H]mesulergine) radioligand binding to the human 5-HT2C receptor with derived Ki values of 3.3 +/- 0.9 and 32 +/- 6 nM, respectively. Relative to 5-HT2C receptor binding, WAY-161503 was approximately 6-fold less potent at human 5-HT2A receptors ([125I]DOI) with a derived Ki value of 18 nM and 20-fold less potent at human 5-HT2B receptors ([3H]5-HT) with a derived Ki value of 60 nM. In functional studies, WAY-161503 was a full agonist in stimulating 5-HT2C-receptor-coupled [3H]inositol phosphate (IP) formation and calcium mobilization with EC50 values of 8.5 nM and 0.8 nM, respectively. WAY-161503 was also a 5-HT2B agonist (EC50s 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 (EC50, 802 nM) yet potently stimulated calcium mobilization (EC50, 7 nM) in 5-HT2A receptor-expressing cells. Functionally, WAY-161503 also stimulated the phospholipase A2-coupled arachidonic acid release in 5-HT2C receptor expressing cells albeit with lower potency (EC50, 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 ED50 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-HT2C 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.
Rosenzweig-Lipson
Sharon
S
Discovery Neuroscience, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA. rosenzs@wyeth.com
Zhang
Jean
J
Mazandarani
Hossein
H
Harrison
Boyd L
BL
Sabb
Annmarie
A
Sabalski
Joan
J
Stack
Gary
G
Welmaker
Greg
G
Barrett
James E
JE
Dunlop
John
J
D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D016718:Arachidonic Acid / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004435:Eating / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy*; D010744:Phosphoric Monoester Hydrolases / Q000493:pharmacokinetics; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014316:Tritium / Q000493:pharmacokinetics
C502777:8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino(1,2-a)quinoxalin-5(6H)-one; D019440:Anti-Obesity Agents; D011719:Pyrazines; D011810:Quinoxalines; D058826:Serotonin 5-HT2 Receptor Agonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D014316:Tritium; D016718:Arachidonic Acid; D012701:Serotonin; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase