Abstract
Neuropeptide Y (NPY) regulates physiological processes via receptor subtypes (Y1, Y2, Y4, Y5, and y6). The Y5 receptor is well known for its role in appetite. Based on expression in the limbic system, we hypothesized that the Y5 receptor might also modulate stress sensitivity. We identified a novel Y5 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 Y5 receptors (Ki = 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 Y5 receptor-selective agonist [cPP1-7,NPY19-23,Ala31,Aib32,Gln34]-hPancreatic Polypeptide in Sprague-Dawley rats. In vivo effects of Lu AA33810 were correlated with brain exposure ≥ 50 ng/g and ex vivo Y5 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 [cPP1-7,NPY19-23,Ala31,Aib32,Gln34]-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 Y5 receptors may function as part of an endogenous stress-sensing system to mediate social anxiety and reward or motivational deficits in selected rodent models.
Footnotes
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The authors are affiliated with Lundbeck Research USA as either employees or paid collaborators. Lundbeck has a research program to study the therapeutic potential of the Y5 receptor as a drug target.
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doi:10.1124/jpet.108.144634.
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ABBREVIATIONS: NPY, neuropeptide Y; PYY, peptide YY; PP, pancreatic polypeptide; FMS586, 3-(5,6,7,8-tetrahydro-9-isopropyl-carbazol-3-yl)-1-methyl-1-(2-pyridin-4-yl-ethyl)-urea hydrochloride; Lu AA33810, N-[[trans-4-[(4,5-dihydro[1]benzothiepino[5,4-d]thiazol-2-yl)amino]cyclohexyl]methyl]-methanesulfonamide; HPA, hypothalamic-pituitary-adrenal; Lu AA44608, N-[trans-4-[[[4-(2-pyridinyl)-2-thiazolyl]amino]methyl]cyclohexyl]-2-propanesulfonamide; [35S]Lu AE66516, [35S]1,2-dihydro-1-(methylsulfonyl)-N-(5-phenyl-2-pyrimidinyl)-spiro[3H-indole-3,4′-piperidine]-1′-carboxamide; pNPY, porcine NPY; cPP, [cPP1-7,NPY19-23,Ala31,Aib32,Gln34]-hPancreatic Polypeptide; HEK, human embryonic kidney; DMSO, dimethyl sulfoxide; BSA, bovine serum albumin; 5-HT, 5-hydroxytryptamine; FLIPR, fluorometric imaging plate reader; PK-PD, pharmacokinetic-pharmacodynamic; F344, Fischer 344; RIA, radioimmunoassay; FST, forced swim test; CMS, chronic mild stress; ANOVA, analysis of variance; AUC, area(s) under curve; CI, confidence interval; MK-0557, trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide; FSL, Flinders sensitive line; FRL, Flinders resistant line; Veh, vehicle; CRF, corticotropin releasing factor.
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↵1 Porsolt & Partners, Paris, France.
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↵2 Theravance, Inc., South San Francisco, California.
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↵3 Clinical Pharmacology and Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
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↵4 Transcription Diagnostics, Inc., Mahwah, New Jersey.
- Received August 11, 2008.
- Accepted December 17, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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