title: The novel neuropeptide Y Y5 receptor antagonist Lu AA33810 [N-[[trans-4-[(4,5-dihydro[1]benzothiepino[5,4-d]thiazol-2-yl)amino]cyclohexyl]methyl]-methanesulfonamide] exerts anxiolytic- and antidepressant-like effects in rat models of stress sensitivity.
abstract: Neuropeptide Y (NPY) regulates physiological processes via receptor subtypes (Y(1), Y(2), Y(4), Y(5), and y(6)). The Y(5) receptor is well known for its role in appetite. Based on expression in the limbic system, we hypothesized that the Y(5) receptor might also modulate stress sensitivity. We identified a novel Y(5) receptor-selective antagonist, Lu AA33810 [N-[[trans-4-[(4,5-dihydro[1]-benzothiepino[5,4-d]thiazol-2-yl)amino]cyclohexyl]methyl]-methanesulfonamide], that bound to cloned rat Y(5) receptors (K(i) = 1.5 nM) and antagonized NPY-evoked cAMP and calcium mobilization in vitro. Lu AA33810 (3-30 mg/kg p.o.) blocked feeding elicited by intracerebroventricular injection of the Y(5) receptor-selective agonist [cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]-hPancreatic Polypeptide in Sprague-Dawley rats. In vivo effects of Lu AA33810 were correlated with brain exposure > or = 50 ng/g and ex vivo Y(5) receptor occupancy of 22 to 95%. Lu AA33810 was subsequently evaluated in models of stress sensitivity. In Fischer 344 rats, Lu AA33810 (30 mg/kg p.o.) attenuated increases in plasma ACTH and corticosterone elicited by intracerebroventricular injection of [cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]-hPancreatic Polypeptide. In Sprague-Dawley rats subjected to the social interaction test, Lu AA33810 (3-30 mg/kg p.o.) produced anxiolytic-like effects after acute or chronic treatment. In Flinders sensitive line rats, chronic dosing of Lu AA33810 (10 mg/kg/day i.p.) produced anxiolytic-like effects in the social interaction test, plus antidepressant-like effects in the forced swim test. In Wistar rats exposed to chronic mild stress, chronic dosing of Lu AA33810 (3 and 10 mg/kg/day i.p.) produced antidepressant-like activity, i.e., normalization of stress-induced decrease in sucrose consumption. We propose that Y(5) receptors may function as part of an endogenous stress-sensing system to mediate social anxiety and reward or motivational deficits in selected rodent models.
authors.affiliation: Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, USA. mmw@lundbeck.com
authors.forename: Mary W
authors.initials: MW
authors.lastname: Walker
authors.forename: Toni D
authors.initials: TD
authors.lastname: Wolinsky
authors.forename: Vrej
authors.initials: V
authors.lastname: Jubian
authors.forename: Gamini
authors.initials: G
authors.lastname: Chandrasena
authors.forename: Huailing
authors.initials: H
authors.lastname: Zhong
authors.forename: Xinyan
authors.initials: X
authors.lastname: Huang
authors.forename: Silke
authors.initials: S
authors.lastname: Miller
authors.forename: Laxminarayan G
authors.initials: LG
authors.lastname: Hegde
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Marsteller
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Marzabadi
authors.forename: Mariusz
authors.initials: M
authors.lastname: Papp
authors.forename: David H
authors.initials: DH
authors.lastname: Overstreet
authors.forename: Christophe P G
authors.initials: CP
authors.lastname: Gerald
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Craig
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001582:Benzothiepins / Q000627:therapeutic use*; D004195:Disease Models, Animal; D008297:Male; D008958:Models, Molecular; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D013315:Stress, Psychological / Q000188:drug therapy*; D013449:Sulfonamides / Q000627:therapeutic use*; D013844:Thiazoles / Q000627:therapeutic use*
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D001582:Benzothiepins; C539254:N-((4-((4,5-dihydro(1)benzothiepino(5,4-d)thiazol-2-yl)amino)cyclohexyl)methyl)methanesulfonamide; C539255:N-(4-(((4-(2-pyridinyl)-2-thiazolyl)amino)methyl)cyclohexyl)-2-propanesulfonamide; D017476:Receptors, Neuropeptide Y; D013449:Sulfonamides; D013844:Thiazoles; C100568:neuropeptide Y5 receptor