NPY Y2 and Y4 receptors selective ligands: Promising anti-obesity drugs?

Current Topics in Medicinal Chemistry

Volumn 7, Issue 17, 2007, Pages 1734-1742

  Kamiji, M M ^a   Inui, A ^b  

^a UNIVERSITY OF SÃO PAULO   (Brazil)

^b KAGOSHIMA UNIVERSITY   (Japan)

Author keywords

Appetite regulation; Body weight; Food intake; Neuropeptide Y; Neuropeptide Y receptors; Obesity

Indexed keywords

ANTIOBESITY AGENT; GR 231118; MESSENGER RNA; N [2 [1,2 DIHYDRO 3,5(4H) DIOXO 1,2 DIPHENYL 1,2,4 TRIAZOL 4 YL]ETHYL] N2 [[1 [2 [4 [5,11 DIHYDRO 6(6H) OXODIBENZ[B,E]AZEPIN 11 YL] 1 PIPERAZINYL] 2 OXOETHYL]CYCLOPENTYL]ACETYL]ARGININAMIDE; NEUROPEPTIDE Y; NEUROPEPTIDE Y [13-36]; NEUROPEPTIDE Y RECEPTOR AGONIST; NEUROPEPTIDE Y RECEPTOR ANTAGONIST; NEUROPEPTIDE Y1 RECEPTOR; NEUROPEPTIDE Y2 RECEPTOR; NEUROPEPTIDE Y2 RECEPTOR ANTAGONIST; NEUROPEPTIDE Y4 RECEPTOR; PANCREAS POLYPEPTIDE; PEPTIDE YY; TM 30338; UNCLASSIFIED DRUG; LIGAND; NEUROPEPTIDE Y RECEPTOR;

AMINO ACID SEQUENCE; AMINO ACID SUBSTITUTION; BINDING SITE; BLOOD BRAIN BARRIER; BRAIN REGION; CLINICAL TRIAL; COMPETITIVE INHIBITION; DIET RESTRICTION; DRUG RECEPTOR BINDING; DRUG SAFETY; DRUG STRUCTURE; DRUG TOLERABILITY; GENE EXPRESSION; GENETIC VARIABILITY; HOMOZYGOSITY; HUMAN; LIGAND BINDING; NONHUMAN; OBESITY; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; REVIEW; WEIGHT REDUCTION; ANIMAL; DRUG ANTAGONISM; DRUG EFFECT; FEEDING BEHAVIOR; METABOLISM; PHYSIOLOGY;

ANIMALS; ANTI-OBESITY AGENTS; FEEDING BEHAVIOR; HUMANS; LIGANDS; OBESITY; RECEPTORS, NEUROPEPTIDE Y;

EID: 36248988601     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/156802607782340957     Document Type: Review

References (122)

1. Hokfelt, T.; Broberger, C.; Zhang, X.; Diez, M.; Kopp, J.; Xu, Z.; Landry, M.; Bao, L.; Schalling, M.; Koistinaho, J.; DeArmond, S. J.; Prusiner, S.; Gong, J.; Walsh, J. H. Neuropeptide Y: some viewpoints on a multifaceted peptide in the normal and diseased nervous system. Brain Res. Brain Res. Rev. 1998, 26, 154-166.
2. Larhammar, D.; Wraith, A.; Berglund, M. M.; Holmberg, S. K. S.; Lundell, I. Origins of the multiple NPY-flimily receptors in mammals. Peptides 2001, 22, 295-307.
3. Larhammar, D.; Fredriksson, R.; Larson, E. T.; Salaneck, E. Phylogeny of NPY-family peptides and their receptors. In: Neuropeptide Y and Related Peptides; Michel, M. C.; Ed.; Springer-Verlag: Berlin-Heidelberg, 2004; pp 75-100.
4. Michel, M. C.; Beck-Sickinger, A.; Cox, H.; Doods, H. N.; Herzog, H.; Larhammar, D.; Quirion, R.; Schwartz, T.; Westfall, T. XVI International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors. Pharmacol. Rev. 1998, 50, 143-150.
5. Zimanyi, I. A.; Fathi, Z.; Poindexter, G. S. Central control of feeding behavior by neuropeptide Y. Curr. Pharm. Des. 1998, 4, 349-366.
6. Bromee, T.; Sjodin, P.; Fredriksson R.; Boswell, T.; Larsson, T. A.; Salaneck, E.; Zoorob, R.; Mohell, N.; Larhammar, D. Neuropeptide Y-family receptors Y6 and Y7 in chicken. Cloning, pharmacological characterization, tissue distribution and conserved synteny with human chromosome region. FEBS J. 2006, 273, 2048-2063.
7. Sainsbury, A.; Baldock, P. A.; Schwarzer, C.; Ueno, N.; Enriquez, R. F.; Couzens, M.; Inui, A.; Herzog, H.; Gardiner, E. M. Synergistic effects of Y2 and Y4 receptors on adiposity and bone mass revealed in double knockout mice. Mol. Cell Biol. 2003, 23, 5225-5233.
8. Gehlert, D. R.; Gackenheimer, S.; L. Differential distribution of neuropeptide Y Y1 and Y2, receptors in rat and guinea-pig brains. Neuroscience 1997, 76, 215-224.
9. Lin, S.; Boey, D.; Herzog, H. NPY and Y receptors: lessons from transgenic and knockout models. Neuropeptides 2004, 38, 189-200.
10. Fredriksson, R.; Larson, E. T.; Yan, Y-L.; Postlethwaite, J. H.; Larhammar, D. Novel neuropeptide Y Y2-like receptor subtype in zebrafish and frogs supports early vertebrate chromosome duplications. J. Mol. Evol. 2004, 58, 106-114.
11. Larsson, T. A.; Larson, E. T.; Fredriksson, R.; Conlon, J. M.; Larhammar, D. Characterization of NPY receptor subtypes Y2 and Y7 in rainbow trout Oncorhynchus mykiss. Peptides 2006, 27, 1320-1327.
12. Campbell, R. E.; Smith, M. S.; Allen, S. E.; Grayson, B. E.; Ffrench-Mullen, J. M.; Grove, K. L. Orexin neurons express a functional pancreatic polypeptide Y4 receptor. J. Neurosci. 2003, 23, 1487-1497.
13. Parker, R. M.; Herzog, H. Regional distribution of Y-receptor subtype mRNAs in rat brain. Eur. J. Neurosci. 1999, 11, 1431-1448.
14. Dumont, Y.; Martel, J-C.; Fournier, A.; St-Pierre, S.; Quirion, R. Neuropeptide Y and neuropeptide Y receptor subtypes in brain and peripheral tissues. Prog. Neurobiol. 1992, 38, 125-167.
15. Berglund, M. M.; Hipskind, P. A.; Gehlert D. R. Recent developments in our understanding of the physiological role of PP-fold peptide receptor subtypes. Exp. Biol. Med. (Maywood). 2003, 228, 217-244.
16. Cabrele, C.; Beck-Sickinger, A. G. Molecular characterization of the ligand-receptor interaction of the neuropeptide Y family. J. Pept. Sci. 2000, 6, 97-122.
17. Clark, J. T.; Keaton, A. K.; Sahu, A.; Kalra, S. P.; Mahajan, S. C.; Gudger, J. N. Neuropeptide Y (NPY) levels in alcoholic and food restricted male rats: implications for site selective function. Regul. Pept. 1998, 75-76, 335-345.
18. Kalra, S. P.; Dube, M. G.; Pu, S.; Xu, B.; Horvath, T. L.; Kalra, P. S. Interacting appetite-regulating pathways in the hypothalamic regulation ofbody weight. Endocr. Rev. 1999, 20, 68-100.
19. Inui, A. Neuropeptide gene polymorphisms and human behavioural disorders. Nat. Rev. Drug Discov. 2003, 2, 986-998.
20. Day, D. E.; keen-Rhinehart, E.; Bartness, T. J. Role of NPY and its receptor subtypes in foraging, food hoarding, and food intake by Siberian hamsters. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2005, 289, R29-36.
21. Brady, L. S.; Smith, M. A.; Gold, P. W.; Herkenham, M. Altered expression of hypothalamic neuropeptide mRNAs in food-restricted and food-deprived rats. Neuroendocrinology 1990, 52, 441-447.
22. Lewis, D. E.; Shellard, L.; Koeslag, D. G.; Boer, D. E.; McCarthy, H. D.; McKibbin, P. E.; Russell, J. C.; Williams, G. Intense exercise and food restriction cause similar hypothalamic neuropeptide Y increases in rats. Am. J. Physiol. 1993, 264; E279-284.
23. Xu, B.; Kalra, P. S.; Farmerie, W. G.; Kalra, S..P. Daily changes in hypothalamic gene expression of neuropeptide Y, galanin, proopiomelanocortin, and adipocyte leptin gene erpression and secretion: effects of food restriction. Endocrinology 1999, 140, 2868-2875.
24. Bi, S.; Robinson, B. M.; Moran, T. H. Acute food deprivation and chronic food restriction differentially affect hypothalamic NPY mRNA expression. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2003, 285, R1030-6.
25. Beck, B.; Jhanwar-Uniyal, M.; Burlet, A.; Chapleur-Chateau, M.; Leibowitz, S. F.; Burlet, C. Rapid and localized alterations of neuropeptide Y in discrete hypothalamic nuclei with feeding status. Brain Res. 1990, 528, 245-249.
26. Clark, J. T.; Kalra, P. S.; Crowley, W. R.; Kalra, S. P. Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 1984, 115, 427-429.
27. Stanley, B. G.; Leibowitz, S. F. Neuropeptide Y: stimulation of feeding and drinking by injection into the paraventricular nucleus. Life Sci. 1994, 35, 2635-2642.
28. Levine, A. S.; Morley, J. E. Neuropeptide Y: a potent inducer of consummatory behavior in rats. Peptides 1984, 5, 1025-1029.
29. Clark, J. T.; Sahu, A.; Kalra, P. S.; Balasubramaniam, A.; Kalra, S. P. Neuropeptide Y (NPY)-induced feeding behavior in female rats: comparison with human NPY ([Met17NPY), NPY analog ([norLeu4]NPY) and peptide YY. Regul. Pept. 1987, 17, 31-39.
30. Stricker-Krongrad, A.; Beck, B.; Burlet, C. Enhanced feeding response to neuropeptide Y in hypothalamic neuropeptide Y-depleted rats. Eur. J. Pharmacol. 1996, 295, 27-34.
31. Flynn, M. C.; Plata-Salaman, C. R.; Ffrench-Mullen, J. M. Neuropeptide Y-related compounds and feeding. Physiol. Behav. 1999, 65, 901-905.
32. Raposinho, P. D.; Pierroz, D. D.; Broqua, P.; White, R. B.; Pedrazzini, T.; Aubert, M. L. Chronic administration of neuropeptide Y into the lateral ventricle of C57BL/6J mate mice produces an obesity syndrome including hyperphagia, hyperleptinemia, insulin resistance, and hypogonadism. Mol. Cell Endocrinol. 2001, 185, 195-204.
33. Boss-Williams, K. A.; Bartness, T. J. NPY stimulation of food intake in Siberian hamsters is not photoperiod dependent. Physiol. Behav. 1996, 59, 157-64.
34. Henry, M.; Ghibaudi, L.; Gao, J.; Hwa, J. J. Energy metabolic profile of mice after chronic activation of central NPY Y1, Y2, or Y5 receptors. Obes. Res. 2005, 13, 36-47.
35. Sainsbury, A.; Bergen, H. T.; Boey, D.; Bamming, D.; Cooney, G. J.; Lin, S.; Couzens, M.; Stroth, N.; Lee, N. J.; Lindner, D.; Singewald, N.; Karl, T.; Duffy, L.; Enriquez, R.; Stack, K.; Sperk, G.; Herzog, H. Y2Y4 receptor double knockout protects against obesity due to a high-fat diet or Y1 receptor deficiency in mice. Diabetes 2006, 55, 19-26.
36. Asakawa, A.; Inui, A.; Yuzuriha, H.; Ueno, N.; Katsuura, G.; Fujimiya, M.; Fujino, M. A.; Niijima, A.; Meguid, M. M.; Kasuga, M. Characterization of the effects of pancreatic polypeptide in the regulation of energy balance. Gastroenterology 2003, 124, 1325-1336.
37. Le Roux, C. W.; Bloom, S. R. Peptide YY, appetite and food intake. Proc. Nutr. Soc. 2005, 64, 213-216.
38. Zagorsky, J. L. Health and wealth. The late-20th century obesity epidemic in the U.S. Econ. Hum. Biol. 2005, 3, 296-313.
39. Cairns, E. Obesity: the fat lady sings? Drug Discov. Today 2005, 10, 305-307.
40. Batterham, R. L.; Le Roux, C. W.; Cohen, M. A.; Park, A. J.; Ellis, S. M.; Patterson, M.; Frost, G. S.; Ghatei, M. A, Bloom SR. Pancreatic polypeptide reduces appetite and food intake in humans. J. Clin. Endocrinol. Metab. 2003, 88, 3989-3992.
41. Balasubramaniam, A.; Mullins, D. E.; Lin, S.; Zhai, W.; Tao, Z.; Dhawan, V. C.; Guzzi, M.; Knittel, J. J.; Slack, K.; Herzog, H.; Parker, E. M. Neuropeptide Y (NPY) Y4 receptor selective agonists based on NPY(32-36): development of an anorectic Y4 receptor selective agonist with picomolar affinity. J. Med. Chem. 2006, 49, 2661-2665.
42. Hung, C. C.; Pirie, F.; Luan, J.; Lank, E.; Motala, A.; Yeo, G. S.; Keogh, J. M.; Wareham, N. J.; O'Rahilly, S.; Farooqi, I. S. Studies of the peptide YY and neuropeptide Y2 receptor genes in relation to human obesity and obesity-related traits. Diabetes 2004, 53, 2461-2466.
43. Ma, L.; Tataranni, P. A.; Hanson, R. L.; Infante, A, M.; Kobes, S.; Bogardus, C.; Baier, L. J. Variations in peptide YY and Y2 receptor genes are associated with severe obesity in Pima Indian men. Diabetes 2005, 54, 1598-602.
44. Lavebratt, C.; Alpman, A.; Persson, B.; Arner, P.; Hoffstedt, J. Common neuropeptide Y2 receptor gene variant is protective against obesity among Swedish men. Int. J. Obes. (Lond). 2006, 30, 453-459.
45. Dumont, Y.; Cadieux, A.; Doods H, Pheng LH, Abounader R, Hamel E, Jacques D, Regoli D, Quirion R. BHE0246, a potent and highly selective non-peptide neuropeptide Y Y(2) receptor antagonist. Br. J. Pharmacol. 2000, 129, 1075-1088.
46. Dumont, Y.; Jacques, D.; Bouchard, P.; Quirion, R. Species differences in the expression and distribution of the neuropeptide Y Y1, Y2, Y4, and Y5 receptors in rodents, guinea pig, and primates brains. J. Comp. Neurol. 1998, 402, 372-384.
47. Jacques, D.; Dumont, Y.: Fournier, A.; Quirion, R. Characterization of neuropeptide Y receptor subtypes in the normal human brain, including the hypothalamus. Neuroscience 1997, 79, 129-148.
48. Gustafson, E. L.; Smith, K. E.; Durkin, M. M.; Walker, M. W.; Gerald, C.; Weinshank, R.; Branchek, T. A. Distribution of the neuropeptide Y Y2 receptor mRNA in rat central nervous system. Brain Res. Mol. Brain Res. 1997, 46, 223-235.
49. Broberger, C.; Landry, M.; Wong, H.; Walsh, J. N.; Hokfelt, T. Subtypes Y1 and Y2 of the neuropeptide Y receptor are respectively expressed in pro-opiomelanocortin- and neuropeptide-Y-containing neurons of the rat hypothalamic arcuate nucleus Neuroendocrinology 1997, 66, 393-408.
50. Parker, R. M.; Herzog, H. Regional distribution of Y-receptor subtype mRNAs in rat brain. Eur. J. Neurosci. 1999, 11, 1431-1449.
51. Fetissov, S. O.; Byrne, L. C.; Hassani, H.; Ernfors, P.; Hokfelt, T. Characterization of neuropeptide Y Y2 and Y5 receptor expression in the mouse hypothalamus. J. Comp. Neurol. 2004, 470, 256-265.
52. Brumovsky, P.; Stanic, D.; Shuster, S.; Herzog, H.; Villar, M.; Hokfelt, T. Neuropeptide Y2 receptor protein is present in peptidergic and nonpeptidergic primary sensory neurons of the mouse. J. Comp. Neurol. 2005, 489, 328-348.
53. Naveilhan, P.; Neveu, I.; Arenas, E.; Ernfors, P. Complementary and overlapping expression of Y1, Y2 and Y5 receptors in the developing and adult mouse nervous system. Neuroscience 1993, 87, 289-302.
54. Caberlotto, L.; Fuxe, K.; Hurd, Y. L. Characterization of NPY mRNA-expressing cells in the human brain: co-localization with Y2 but not Y1 mRNA in the cerebral cortex, hippocampus, amygdala, and striaturn. J. Chem. Neuroanat. 2000, 20, 327-337.
55. King, P. J.; Williams, G.; Doods, H.; Widdowson, P. S. Effect of a selective neuropeptide Y Y(2) receptor antagonist, BIIE0246 on neuropeptide Y release. Eur. J. Pharmacol. 2000, 12, 396, R1-3.
56. Baskin, D. G.; Schwartz, M. W.; Seeley, R. J.; Woods, S. C.; Porte, D. Jr.; Breininger, J. F.; Jonak, Z.; Schaefer, J.; Krouse, M.; Burghardt, C.; Campfield, L. A.; Burn, P.; Kochan, J. P. Leptin receptor long-form splice-variant protein expression in neuron cell bodies of the brain and co-localization with neuropeptide Y mRNA in the arcuate nucleus. J. Histochem. Cytochem. 1999, 47, 353-362.
57. Baskin, D. G.; Breininger, J. F.; Schwartz, M. W. Leptin receptor mRNA identifies a subpopulation of neuropeptide Y neurons activated by fasting in rat hypothalamus. Diabetes 1999, 48, 828-833.
58. Broberger, C. Brain regulation of food intake and appetite: molecules and networks, J. Intern. Med. 2005, 258, 301-327.
59. Whitcomb, D. C.; Taylor, I. L.; Vigna, S. R. Cbaracterization of saturable binding sites for circulating pancreatic polypeptide in rat brain. Am. J. Physiol. 1990, 159, G687-691.
60. Dumont, Y.; Quirion, R. [(125)I]-GR231118: a high affinity radioligand to investigate neuropeptide Y Y(1) and Y(4) receptors. Br. J. Pharmacol. 2000, 129, 37-46.
61. Bard, J. A.; Walker, M. W.; Branchck, T. A.; Weinshank., R. L. Cloning and functional expression of a human Y4 subtype receptor for pancreatic polypeptide, neuropeptide Y, and peptide YY. J. Biol. Chem. 1995, 270, 26762-26765.
62. Yan, H.; Yang, J.; Marasco, J.; Yamaguchi, K.; Brenner, S.; Collins, T.; Karbon, W. Cloning and functional expression of cDNAs encoding human and rat pancreatic polypeptide receptors. Proc. Natl. Acad. Sci. USA 1996, 93, 4661-4665.
63. Lundell, I.; Blomqvist, A, G.; Berglund, M. M.; Schober, D. A.; Johnson, D.; Statnick, M. A.; Gadski, R. A.; Gehlert, D. R.; Larhammar, D. Cloning of a human receptor of the NPY receptor family with high affinity for pancreatic polypeptide and peptide YY. J. Biol. Chem. 1995, 270, 29123-29128.
64. Larsen, P. J.; Kristensen, P. The neuropeptide Y (Y4) receptor is highly expressed in neurones of the rat dorsal vagal complex. Brain Res. Mol. Brain Res. 1997, 48, 1-6.
65. Fetissov, S. O.; Kopp, J.; Hokfelt, T. Distribution of NPY receptors in the hypothalamus. Neuropeptides 2004, 38, 175-188.
66. Hoyle, C. H. V. Neuropeptide families and their receptors: Evolutionary perspectives. Brain Res. 1999, 848, 1-25.
67. Larhammar, D. Evolution of neuropeptide Y. peptide YY, and pancreatic polypeptide. Regul. Pept. 1999, 62, 1-11.
68. Larhammar, D. Extraordinary structural diversity of NPY-family receptors. In Neuropeptide Y and Drug Development; Grundemar L.; Bloom G.; Eds.; Academic Press: San Diego, 1997; pp 87-105.
69. Berglund, M. M.; Hipskind, P. A.; Gehlert, D. R. Recent developments in our understanding of the physiological role or PP-fold peptide receptor subtypes. Exp. Biol. Med. (Maywood) 2003, 228, 217-244.
70. Fuhlendorff, J.; Gether, U.; Aakerlund, L.; Langeland-Johansen, N.; Thogersen, H.; Melberg, S. G.; Olsen, U. B.; Thastrup, O.; Schwartz, T. W. [Leu31, Pro34]neuropeptide Y: a specific Y1 receptor agonist. Proc. Natl. Acad. Sci. US4 1990, 87, 182-186.
71. Potter, E. K.; McCloskey, M. J. [Leu31, Pro34]NPY, a selective functional postjunctional agonist at neuropeptide-Y receptors in anaesthetised rats. Neurosci. Lett. 1992, 134, 183-186.
72. Potter, E. K.; Fuhlendorff, J.; Schwartz, T. W. [Pro34]neuropeptide Y selectively identifies postjunctional-mediated actions of neuropeptide Y in vivo in rats and dogs. Eur. J. Pharmacol. 1991, 193, 15-19.
73. Doods, H.; Gaida, W.; Wieland, H. A.; Dollinger, H.; Schnorrenberg, G.; Esser, F.; Engel, W.; Eberlein, W.; Rudolf, K. BIIE0246: a selective and high affinity neuropeptide Y Y2 receptor antagonist. Eur. J. Pharmacol. 1999, 384, R3-R5.
74. Smith-White, M. A., Hardy, T. A., Brock, J. A., Potter, E. K. Effects of a selective neuropeptide Y Y2 receptor antagonist, BIIE0246, on Y2 receptors at peripheral neuroeffector junctions. Br. J. Pharmacol. 2001, 132, 861-868.
75. Malmstrom, R. E. Vascular pharmacology of BIIE0246, the first selective non-peptide neuropeptide Y Y(2) receptor antagonist, in vivo. Br. J. Pharmacol. 2001, 133, 1073-1080.
76. Malmstrom, R. E.; Lundberg, J. O.; Weitzberg, E. Autoinhibitory function of the sympathetic prejunctional neuropeptide Y Y(2) receptor evidenced by BIIE0246. Eur. J. Pharmacol. 2002, 439, 113-119.
77. Malmstrom, R.E., Lundberg, J. O. N.; Weitzberg, E. Effects of the neuropeptide Y Y2 receptor antagonist BIIE0246 on sympathetic transmitter release in the pig in vivo. Naunyn-Schmiedeberg's Arch. Pharmacol. 2002, 365, 106-111.
78. Nakajima, M.; Inui, A.; Asakawa, A.; Momose, K.; Ueno, N.; Teranishi, A.; Baba, S.; Kasuga, M. Neuropeptide Y produces anxiety via Y2-type receptors. Peptides 1998; 19, 359-363.
79. Sajdyk, T.J.; Schober, D.A.; Smiley, D.L; Gehlert, D. R. Neuropeptide Y-Y2 receptors mediate anxiety in the amygdala. Pharmacol. Biochem. Behav. 2002, 71, 419-423.
80. Kask, A.; Rago, L.; Harro, J. Anxiolytic-like effect of neuropeptide Y (NPY) and NPY13-36 microinjected into vicinity of locus coeruleus in rats. Brain Res. 1998, 788, 345-348.
81. Tschenett, A.; Singewald, N.; Carli, M.; Balducci, C.; Salchner, P.; Vezzani, A.; Herzog, H.; Sperk, G. Reduced anxiety and improved stress coping ability in mice lacking NPY-Y2 receptors. Eur. J. Neurosci. 2003, 18, 143-148.
82. Redrobe, J. P.; Dumont, Y.; Herzog, H.; Quirion, R. Neuropeptide Y (NPY) Y2 receptors mediate behaviour in two animal models of anxiety: evidence from Y2 receptor knockout mice. Behav. Brain Res. 2003, 141, 251-255.
83. Greco, B.; Carli, M. Reduced attention and increased impulsivity in mice lacking NPY Y2 receptors: relation to anxiolytic-like phenotype. Behav. Brain Res. 2006, 169, 325-334.
84. Carvajal, C.; Dumont, Y.; Herzog, H.; Quirion, R. Emotional behavior in aged neuropeptide Y (NPY) Y2 knockout mice. J. Mol. Neurosci. 2006, 28, 239-245.
85. Golombek, D. A.; Biello, S. M.; Harrington, ME. Neuropeptide Y phase shifts the circadian clock via a Y2 receptor. Neuroreport 1996, 7, 1315-1319.
86. Huhman, K. L.; Gillespie, C. F.; Marvel, C. L.; Albers, H. E. Neuropeptide Y phase shifts circadian rhythms in vivo via a Y2 receptor. Neuroreport 1996, 7, 1249-1252.
87. Wultsch, T.; Painsipp, E.; Donner, S.; Sperk, G.; Herzog, H.; Peskar, B. A.; Holzer, P. Selective increase of dark phase water intake in neuropeptide-Y Y2 and Y4 receptor knockout mice. Behav. Brain Res. 2006, 168, 255-260.
88. Baldock, P. A.; Sainsbury, A.; Allison, S.; Lin, E.-J.; Couzens, M.; Boey, D.; Enriquez, R.; During, M.; Herzog, H.; Gardiner, E. M. Hypothalamic control of bone formation: distinct actions of leptin and y2 receptor pathways. J. Bone Minor. Res. 2005, 20, 1851-1857.
89. Ishiguchi, T.; Amano, T.; Matsubayashi, H.; Tada, H.; Fujita, M.; Takahashi, T. Centrally administered neuropeptide Y delays gastric emptying via Y2 receptors in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2001, 281, R1522-1530.
90. Fujimiya, M.; Itoh, E.; Kihara, N.; Yamamoto, I.; Fujimura, M.; Inui, A. Neuropeptide Y induces fasted pattern of duodenal motility via Y(2) receptors in conscious fed rats. Am. J. Physiol. Gastrointest. Liver Physiol. 2000, 278, G32-38.
91. Walker M. W.; Smith K. E.; Bard J., Vaysse, P. J.; Gerald, C.; Daouti, S.; Weinshank, R. L.; Branchek, T. A. A structure-activity analysis of the cloned rat and human Y4 receptors for pancreatic polypeptide. Peptides 1997, 18:609-612.
92. Tough, I. R.; Holliday, N. D.; Cox, H. M. Y4 receptors mediate the inhibitory responses of pancreatic polypeptide in human and mouse colon mucosa. J. Pharmacol. Exp. Ther. 2006, 319:20-30.
93. Daniels, A. J.; Matthews, J. E.; Slepetis, R. J.; Jansen, M.; Viveros, O. H.; Tadepalli, A.; Harrington, W.; Heyer, D.; Landavazo, A.; Leban, J. J.; Spaltenstein, A. High-affinity neuropeptide Y receptor antagonists. Proc. Natl. Acad Sci. USA 1995, 92, 9067-9071.
94. Balasubramaniam, A.; Zhai, W.; Shoriff, S.; Tao, Z.; Chance, W. T.; Fischer, J. E.; Eden, P. E.; Taylor, J. Bis(31/ 31′)-{[Cys31,Trp32,Nva34]NPY(31-36)}: A Specific NPY Y-1 receptor antagonist. J. Med. Chem. 1996, 39, 811-813.
95. Schober, D. A.; Van Abbema, A. M.; Smiley, D. L.; Bruns, R. F.; Gehlert, D. R. The neuropeptide Y Y1 antagonist, 1229U91, a potent agonist for the human pancreatic polypeptide-preferring (NPY Y4) receptor. Peptides 1998, 19, 537-542.
96. Parker, E. M.; Babji, C. K.; Balasubramaniam, A.; Burrier, R. E.; Guzzi, M.; Hamud, F.; Mukhopadhyay, G.; Rudinski, M. S.; Tao, Z.; Tice, M.; Xia, L.; Mullins, D. E.; Salisbury, B. G. GR231118 (1229U91) and other analogues of the C-terminus of neuropeptide Y are potent neuropeptide Y1 receptor antagonists and neuropeptide Y4 receptor agonists. Eur. J. Pharmacol. 1998, 349, 97-105.
97. Schober, D. A.; Gackenheimer, S. L.; Heiman, M. L.; Gehlert, D. R. Pharmacological characterization of (125)I-1229U91 binding to Y1 and Y4 neuropeptide Y/Peptide YY receptors. J. Pharmacol. Exp. Ther. 2000, 293, 275-280.
98. Wultsch, T.; Painsipp, E., Thoeringer, C. K.; Herzog, H.; Sperk, G.; Holzer, P. Endogenous neuropeptide Y depresses the afferent signaling of gastric acid challenge to the mouse brainstem via neuropeptide Y type Y2 and Y4 receptors. Neuroscience 2005, 136, 1097-1107.
99. Parker, S. L.; Kane, J. K.; Parker, M. S.; Berglund, M. M.; Lundell, I. A.; Li, M. D. Cloned neuropeptide Y (NPY) Y1 and pancreatic polypeptide Y4 receptors expressed in Chinese hamster ovary cells show considerable agonist-driven internalization, in contrast to the NPY Y2 receptor. Eur. J. Biochem. 2001, 268, 877-886.
100. Parker, M. S.; Sah, R.; Sheriff, S.; Balasubramaniam, A.; Parker, S. L. Internalization of cloned pancreatic polypeptide receptors is accelerated by all types of Y4 agonists. Regul. Pept. 2005, 132, 91-101.
101. Voisin, T.; Goumain, M.; Lorinet, A. M.; Maoret, J. J.; Laburthe, M. Functional and molecular properties of the human recombinant Y4 receptor: resistance to agonist-promoted desensitization. J. Pharmacol. Exp. Ther. 2000 292, 638-646.
102. Berglund, M. M.; Schober, D. A.; Esterman, M. A.; Gehlert, D. R. Neuropeptide Y Y4 receptor homodimers dissociate upon agonist stimulation. J. Pharmacol. Exp. Ther. 2003, 307, 1120-1126.
103. Schimidt, P. T.; Naslund, E.; Gryback, P.; Jacobsson, H.; Holst, J. J.; Hilsted, L.; Hellstrom, P. M. A role for pancreatic polypeptide in the regulation of gastric emptying and short-term metabolic control. J. Clin. Endocrinol. Metab. 2005, 90, 5241-5246.
104. Katsuura, G.; Asakawa, A.; Inui, A. Roles of pancreatic polypeptide in regulation of food intake. Peptides 2002, 23, 323-329.
105. Ueno, N.; Inui, A; Iwamoto, M.; Kaga, T.; Asakawa, A.; Okita, M.; Fujimiya, M.; Nakajima, Y.; Ohmoto, Y.; Ohnaka, M.; Nakaya, Y.; Miyazaki, J. I.; Kasuga, M. Decreased food intake and body weight in pancreatic polypeptide-overexpressing mice. Gastroenterology 1999, 117, 1427-1432.
106. Inui, A. Transgenic approach to the study of body weight regulation. Pharmacol. Rev. 2000, 52, 35-61.
107. Naveilhan, P.; Hassani, H.; Canals, J. M.; Ekstrand, A. J.; Larefalk, A.; Chhajlani, V.; Arenas, E.; Gedda, K.; Svensson, L.; Thoren, P.; Ernfors, P. Normal feeding behavior, body weight and leptin response require the neuropeptide Y Y2 receptor. Nat. Med. 1999, 5, 1188-1193.
108. Batterham, R. L.; Cowley, M. A.; Small, C. J.; Herzog, H.; Cohen, M. A.; Dakin, C. L.; Wren, A. M.; Brynes, A. E.; Low, M. J.; Ghatei, M. A.; Cone, R. D.; Bloom, S. R. Gut hormone PYY(3-36) physiologically inhibits food intake. Nature 2002, 418, 650-654.
109. Sainsbury, A.; Schwarzer, C.; Couzens, M.; Fitissov, S.; Furtinger, S.; Jenkins, A.; Cox, H. M.; Sperk, G.; Hokfelt, T.; Herzog, H. Important role of hypothalamic Y2 receptors in bodyweight regulation revealed in conditional knockout mice. Proc. Natl. Acad. Sci. USA. 2002, 99, 8938-8943.
110. Sainsbury, A.; Schwarzer, C.; Couzens, M.; Herzog, H. Y2 receptor deletion attenuates the type 2 diabetic syndrome of ob/ob mice. Diabetes 2002, 51, 3420-3427.
111. Naveilhan, P.; Svensson, L.; Nystrom, S.; Ekstrand, A. J.; Ernfors, P. Attenuation of hypercholesterolemia and hyperglycemia in ob/ob mice by NPY Y2 receptor ablation. Peptides 2002, 23, 1087-109130.
112. Sainsbury, A.; Schwarzer, C.; Couzens, M.; Jenkins, A.; Oakes, S. R.; Ormandy, C. J.; Herzog, H. Y4 receptor knockout rescues fertility in ob/ ob mice. Genes Dev. 2002, 16, 1077-1088.
113. Sainsbury, A.; Baldock, P. A.; Schwarzer, C.; Ueno, N.; Enriquez, R. F.; Couzens, M.; Inui, A.; Herzog, H.; Gardiner, E. M. Synergistic effects of Y2 and Y4 receptors on adiposity and bone mass revealed in double knockout mice. Mol. Cell Biol. 2003, 23, 5225-5233.
114. Goumain, M.; Voisin, T.; Lorinet, A. M.; Ducroc, R.; Tsocas, A.; Roze, C.; Rouet-Benzineb, P.; Herzog, H.; Balasubramaniam, A.; Laburthe, M. The peptide YY-preferring receptor mediating inhibition of small intestinal secretion is a peripheral Y(2) receptor: pharmacological evidence and molecular cloning. Mol. Pharmacol. 2001, 60, 124-134.
115. Lin, S.; Boey, D.; Couzens, M.; Lee, N.; Sainsbury, A.; Herzog, H. Compensatory changes in [125I]-PYY binding in Y receptor knockout mice suggest the potential existence of further Y receptor(s). Neuropeptides 2005, 39, 21-28.
116. Moran, T. H. Pancreatic polypeptide: more than just another gut hormone? Gastroenterology 2003, 124: 1542-1544.
117. Lin, E. J.; Sainsbury, A.; Lee, N. J.; Boey, D.; Couzens, M.; Enriquez, R.; Slack, K.; Bland, R.; During, M. J.; Herzog, H. Combined deletion of Y1, Y2 and Y4 receptors prevents hypothalamic NPY overexpression-induced hyperinsulinemia despite persistence of hyperphagia and obesity. Endocrinology 2006, 147, 5094-5101.
118. Gao, J.; Ghibaudi, L.; Hwa, J. J. Selective activation of central NPY Y1 vs. Y5 receptor elicits hyperinsulinemia via distinct mechanisms. Am. J. Physiol. Endocrinol. Metab. 2004, 287, E706-711.
119. Weyer, C.; Salbe, A. D.; Lindsay, R. S.; Pratley, R. E.; Bogardus, C.; Tataranni, P. A. Exaggerated pancreatic polypeptide secretion in Pima Indians: can an increased parasympathetic drive to the pancreas contribute to hyperinsulinemia, obesity, and diabetes in humans? Metabolism 2001, 50, 223-230.
120. Koska, J.; DelParigi, A.; de Courten, B.; Weyer, C.; Tataranni, P. A. Pancreatic polypeptide is involved in the regulation of body weight in pima Indian male subjects. Diabetes 2004, 53, 3091-3096.
121. Reinehr, T.; Enriori, P. J.; Harz, K.; Cowley, M. A.; Roth, C. L. Pancreatic polypeptide in obese children before and after weight loss. Int. J. Obes. (Lond). 2006, 30, 1476-1481.
122. Diaz-Cabiale, Z.; Parrado, C.; Rivera, A.; de la Calle, A.; Agnati, L.; Fuxe, K.; Narvaez, J. A. Galanin-neuropeptide Y (NPY) interactions in central cardiovascular control: involvement of the NPY Y receptor subtype. Eur. J. Neurosci. 2006, 24, 499-508.