WAY-163909 [(7bR, 10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole], a novel 5-hydroxytryptamine 2C receptor-selective agonist with anorectic activity.
The pharmacological profile of WAY-163909 [(7bR, 10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole], a novel 5-hydroxytryptamine (HT)(2C) (serotonin) receptor-selective agonist is presented. WAY-163909 displaced [(125)I]2,5-dimethoxy-4-iodoamphetamine binding from human 5-HT(2C) receptor sites, in Chinese hamster ovary (CHO) cell membranes, with a K(i) value of 10.5 +/- 1.1 nM. Binding affinities determined for the human 5-HT(2A) and 5-HT(2B) receptor subtypes were 212 and 485 nM, respectively. In functional studies, WAY-163909 stimulated the mobilization of intracellular calcium in CHO cells stably expressing the human 5-HT(2C) receptor with an EC(50) value of 8 nM, and E(max) relative to 5-HT of 90%. WAY-163909 failed to stimulate calcium mobilization in cells expressing the human 5-HT(2A) receptor subtype (EC(50) >> 10muM) and was a 5-HT(2B) receptor partial agonist (EC(50) 185 nM, E(max) 40%). WAY-163909 exhibited negligible affinity (<50% inhibition at 1 muM) for other receptor sites examined, including human 5-HT(1A), D2, and D3 receptors, and the 5-HT transporter binding site in rat cortical membranes. WAY-163909 exhibited weak affinity for the human D4 (245 nM) and 5-HT(7) (343 nM) receptor subtypes and the alpha1 binding site in rat cortical membranes (665 nM). WAY-163909 produced a dose-dependent reduction in food intake in normal Sprague-Dawley rats (ED(50) = 2.93 mg/kg), an effect blocked by a 5-HT(2C) receptor antagonist but not by a 5-HT(2A) or 5-HT(2B) receptor antagonist. In addition, WAY-163909 decreased food intake in obese Zucker rats and diet-induced obese mice with ED(50) values of 1.4 and 5.19 mg/kg i.p., respectively, consistent with the potential utility of 5-HT(2C) receptor agonists as anti-obesity agents.
Dunlop
John
J
Discovery Neuroscience, Wyeth Research, Princeton, NJ 08543, USA. dunlopj@wyeth.com
Sabb
Annmarie L
AL
Mazandarani
Hossein
H
Zhang
Jean
J
Kalgaonker
Sachin
S
Shukhina
Eugenia
E
Sukoff
Stacey
S
Vogel
Robert L
RL
Stack
Gary
G
Schechter
Lee
L
Harrison
Boyd L
BL
Rosenzweig-Lipson
Sharon
S
D000818:Animals; D001067:Appetite Depressants / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001381:Azepines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
C501656:1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta(b)(1,4)diazepino(6,7,1hj)indole; D001067:Appetite Depressants; D001381:Azepines; D007211:Indoles; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists