Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults

Cell Metabolism

Volumn 4, Issue 4, 2006, Pages 275-282

  Erondu, Ngozi ^a   Gantz, Ira ^a   Musser, Bret ^a   Suryawanshi, Shailaja ^a   Mallick, Madhuja ^a   Addy, Carol ^a   Cote, Josee ^a   Bray, George ^b   Fujioka, Ken ^c   Bays, Harold ^d   Hollander, Priscilla ^e   Sanabria Bohórquez, Sandra M ^a   Eng, WaiSi ^a   Långström, Bengt ^f   Hargreaves, Richard J ^a   Burns, H Donald ^a   Kanatani, Akio ^g   Fukami, Takehiro ^g   MacNeil, Douglas J ^a   Gottesdiener, Keith M ^a   Amatruda, John M ^a   Kaufman, Keith D ^a   Heymsfield, Steven B ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

^b PENNINGTON BIOMEDICAL RESEARCH CENTER   (United States)

^c SCRIPPS CLINIC   (United States)

^d LOUISVILLE METABOLIC AND ATHEROSCLEROSIS RESEARCH CENTER   (United States)

^e BAYLOR UNIVERSITY MEDICAL CENTER   (United States)

^f UPPSALA UNIVERSITY   (Sweden)

^g BANYU PHARMACEUTICAL CO LTD   (Japan)

Author keywords

CHEMBIO; HUMDISEASE; MOLNEURO

Indexed keywords

L 152804; MK 0233; MK 0557; N [1 (2 FLUOROPHENYL) 3 PYRAZOLYL] 3 OXOSPIRO [6 AZAISOBENZOFURAN 1 (3H), 1' CYCLOHEXANE] 4' CARBOXAMIDE; NEUROPEPTIDE Y RECEPTOR ANTAGONIST; NEUROPEPTIDE Y1 RECEPTOR; NEUROPEPTIDE Y5 RECEPTOR; NEUROPEPTIDE Y5 RECEPTOR ANTAGONIST; OPIATE ANTAGONIST; PLACEBO; UNCLASSIFIED DRUG;

ADULT; AGED; ARTICLE; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; DRUG DOSE REGIMEN; DRUG HALF LIFE; DRUG POTENCY; DRUG STRUCTURE; DRUG TARGETING; ENERGY BALANCE; HEADACHE; HOMEOSTASIS; HUMAN; MAJOR CLINICAL STUDY; MALE; MULTICENTER STUDY; NONHUMAN; OBESITY; POSITRON EMISSION TOMOGRAPHY; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; STATISTICAL SIGNIFICANCE; WEIGHT REDUCTION;

ADMINISTRATION, ORAL; ADOLESCENT; ADULT; AGED; ANTI-OBESITY AGENTS; BODY WEIGHT; CYCLOHEXANES; DOSE-RESPONSE RELATIONSHIP, DRUG; DOUBLE-BLIND METHOD; HUMANS; MIDDLE AGED; MOLECULAR STRUCTURE; OBESITY; PLACEBOS; POSITRON-EMISSION TOMOGRAPHY; PYRAZOLES; RECEPTORS, NEUROPEPTIDE Y; SENSITIVITY AND SPECIFICITY; SPIRO COMPOUNDS; STRUCTURE-ACTIVITY RELATIONSHIP; TREATMENT OUTCOME;

EID: 33748920715     PISSN: 15504131     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.cmet.2006.08.002     Document Type: Article

References (43)

1. 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., et al. Gut hormone PYY(3-36) physiologically inhibits food intake. Nature 418 (2002) 650-654
2. Baskin D.G., Breininger J.F., and Schwartz M.W. Leptin receptor mRNA identifies a subpopulation of neuropeptide Y neurons activated by fasting in rat hypothalamus. Diabetes 48 (1999) 828-833
3. Cabrele C., Langer M., Bader R., Wieland H.A., Doods H.N., Zerbe O., and Beck-Sickinger A.G. The first selective agonist for the neuropeptide YY5 receptor increases food intake in rats. J. Biol. Chem. 275 (2000) 36043-36048
4. Clark J.T., Kalra P.S., Crowley W.R., and Kalra S.P. Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 115 (1984) 427-429
5. Cowley M.A., Pronchuk N., Fan W., Dinulescu D.M., Colmers W.F., and Cone R.D. Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron 24 (1999) 155-163
6. Dickson S.L., and Luckman S.M. Induction of c-fos messenger ribonucleic acid in neuropeptide Y and growth hormone (GH)-releasing factor neurons in the rat arcuate nucleus following systemic injection of the GH secretagogue, GH-releasing peptide-6. Endocrinology 138 (1997) 771-777
7. Elias C.F., Saper C.B., Maratos-Flier E., Tritos N.A., Lee C., Kelly J., Tatro J.B., Hoffman G.E., Ollmann M.M., Barsh G.S., et al. Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area. J. Comp. Neurol. 402 (1998) 442-459
8. Elias C.F., Aschkenasi C., Lee C., Kelly J., Ahima R.S., Bjorbaek C., Flier J.S., Saper C.B., and Elmquist J.K. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23 (1999) 775-786
9. Erickson J.C., Clegg K.E., and Palmiter R.D. Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature 381 (1996) 415-421
10. Erickson J.C., Hollopeter G., and Palmiter R.D. Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science 274 (1996) 1704-1707
11. Fukami, T., Kanatani, A., Ishihara, A., Ishii, Y., Takahashi, T., Haga, Y., Sakamoto, T., and Itoh, T. (2004). Spiro Compounds. U.S. patent 6,723,847.
12. Gerald C., Walker M.W., Criscione L., Gustafson E.L., Batzl-Hartmann C., Smith K.E., Vaysse P., Durkin M.M., Laz T.M., Linemeyer D.L., et al. A receptor subtype involved in neuropeptide-Y-induced food intake. Nature 11 (1996) 168-171
13. Hu Y., Bloomquist B.T., Cornfield L.J., DeCarr L.B., Flores-Riveros J.R., Friedman L., Jiang P., Lewis-Higgins L., Sadlowski Y., Schaefer J., et al. Identification of a novel hypothalamic neuropeptide Y receptor associated with feeding behavior. J. Biol. Chem. 271 (1996) 26315-26319
14. Ishihara A., Kanatani A., Okada M., Hidaka M., Tanaka T., Mashiko S., Gomori A., Kanno T., Hata M., Kanesaka M., et al. Blockade of body weight gain and plasma corticosterone levels in Zucker fatty rats using an orally active neuropeptide Y Y1 antagonist. Br. J. Pharmacol. 136 (2002) 341-346
15. Ishihara A., Kanatani A., Maskiko S., Tanaka T., Hidaka M., Gomori A., Iwaasa H., Murai N., Egashira S., Murai T., Mitobe Y., et al. A NPY Y5 antagonist selectively improved the diet-induced obesity. Proc. Natl. Acad. Sci. USA 103 (2006) 7154-7158
16. Kalra S.P., Dube M.G., Pu S., Xu B., Horvath T.L., and Kalra P.S. Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr. Rev. 20 (1999) 68-100
17. Kanatani A., Mashiko S., Murai N., Sugimoto N., Ito J., Fukuroda T., Fukami T., Morin N., MacNeil D.J., Van der Ploeg L.H., et al. Role of the Y1 receptor in the regulation of neuropeptide Y-mediated feeding: comparison of wild-type, Y1 receptor-deficient, and Y5 receptor-deficient mice. Endocrinology 141 (2000) 1011-1016
18. Kanatani A., Ishihara A., Iwaasa H., MacNeil D.J., and Fukami T. Development of NPY antagonists and their anorectic effects. Folia Pharmacologica Japonica 127 (2006) 88-91
19. Katz A., Nambi S.S., Mather K., Baron A.D., Follmann D.A., Sullivan G., and Quon M.J. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J. Clin. Endocrinol. Metab. 85 (2000) 2402-2410
20. Kishi T., Aschkenasi C.J., Choi B.J., Lopez M.E., Lee C.E., Liu H., Hollenberg A.N., Friedman J.M., and Elmquist J.K. Neuropeptide Y Y1 receptor mRNA in rodent brain: distribution and colocalization with melanocortin-4 receptor. J. Comp. Neurol. 482 (2005) 217-243
21. Kumarnsit E., Johnstone L.E., and Leng G. Actions of neuropeptide Y and growth hormone secretagogues in the arcuate nucleus and ventromedial hypothalamic nucleus. Eur. J. Neurosci. 17 (2003) 937-944
22. Kushi A., Sasai H., Koizumi H., Takeda N., Yokoyama M., and Nakamura M. Obesity and mild hyperinsulinemia found in neuropeptide Y-Y1 receptor-deficient mice. Proc. Natl. Acad. Sci. USA 95 (1998) 15659-15664
23. Luquet S., Perez F.A., Hnasko T.S., and Palmiter R.D. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 310 (2005) 683-685
24. MacNeil, D.J., Rogers, I., Weekley, B., Mathers, P., Pisacreta, D., Lodge, K., Hill, S., Klein, H., Szumiloski, J., and Zeng, Z. (2006). A Y5 antagonist causes weight loss in diet-induced obese rhesus monkeys. Keystone Symposium: Gut Hormones and Other Regulators of Appetite, Satiety and Energy Expenditure Santa Fe, NM March 24, 2006.
25. Marsh D.J., Hollopeter G., Kafer K.E., and Palmiter R.D. Role of the Y5 neuropeptide Y receptor in feeding and obesity. Nat. Med. 4 (1998) 718-721
26. Mullins D., Kirby D., Hwa J., Guzzi M., Rivier J., and Parker E. Identification of potent and selective neuropeptide Y Y(1) receptor agonists with orexigenic activity in vivo. Mol. Pharmacol. 60 (2001) 534-540
27. Padwal R., Li S.K., and Lau D.C. Long-term pharmacotherapy for overweight and obesity: a systematic review and meta-analysis of randomized controlled trials. Int. J. Obes. Relat. Metab. Disord. 27 (2003) 1437-1446
28. Parker E.M., Balasubramaniam A., Guzzi M., Mullins D.E., Salisbury B.G., Sheriff S., Witten M.B., and Hwa J.J. [D-Trp(34)] neuropeptide Y is a potent and selective neuropeptide Y Y(5) receptor agonist with dramatic effects on food intake. Peptides 21 (2000) 393-399
29. Parker E., Van Heek M., and Stamford A. Neuropeptide Y receptors as targets for anti-obesity drug development: perspective and current status. Eur. J. Pharmacol. 440 (2002) 173-187
30. Pedrazzini T., Seydoux J., Kunstner P., Aubert J.F., Grouzmann E., Beermann F., and Brunner H.R. Cardiovascular response, feeding behavior and locomotor activity in mice lacking the NPY Y1 receptor. Nat. Med. 4 (1998) 722-726
31. Sawchenko P.E. Toward a new neurobiology of energy balance, appetite, and obesity: the anatomists weigh in. J. Comp. Neurol. 402 (1998) 435-441
32. Schwartz M.W., Sipols A.J., Marks J.L., Sanacora G., White J.D., Scheurink A., Kahn S.E., Baskin D.G., Woods S.C., Figlewicz D.P., et al. Inhibition of hypothalamic neuropeptide Y gene expression by insulin. Endocrinology 130 (1992) 3608-3616
33. Schwartz M.W., Woods S.C., Porte Jr. D., Seeley R.J., and Baskin D.G. Central nervous system control of food intake. Nature 404 (2000) 661-671
34. Stanley B.G., Magdalin W., Seirafi A., Nguyen M.M., and Leibowitz S.F. Evidence for neuropeptide Y mediation of eating produced by food deprivation and for a variant of the Y1 receptor mediating this peptide's effect. Peptides 13 (1992) 581-587
35. Stephens T.W., Basinski M., Bristow P.K., Bue-Valleskey J.M., Burgett S.G., Craft L., Hale J., Hoffmann J., Hsiung H.M., Kriauciunas A., et al. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 377 (1995) 530-532
36. Torgerson J.S., Hauptman J., Boldrin M.N., and Sjostrom L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 27 (2004) 155-161
37. Turnbull A.V., Ellershaw L., Masters D.J., Birtles S., Boyer S., Carroll D., Clarkson P., Loxham S.J., McAulay P., Teague J.L., et al. Selective antagonism of the NPY Y5 receptor does not have a major effect on feeding in rats. Diabetes 51 (2002) 2441-2449
38. Van Gaal L.F., Rissanen A.M., Scheen A.J., Ziegler O., Rossner S., and RIO-Europe Study Group. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 365 (2005) 1389-1397
39. Weintraub M., Hasday J.D., Mushlin A.I., and Lockwood D.H. A double-blind clinical trial in weight control. Use of fenfluramine and phentermine alone and in combination. Arch. Intern. Med. 144 (1984) 1143-1148
40. Weintraub M., Sundaresan P.R., Schuster B., Ginsberg G., Madan M., Balder A., Stein E.C., and Byrne L. Long-term weight control study. II (weeks 34 to 104). An open-label study of continuous fenfluramine plus phentermine versus targeted intermittent medication as adjuncts to behavior modification, caloric restriction, and exercise. Clin. Pharmacol. Ther. 51 (1992) 595-601
41. Willesen M.G., Kristensen P., and Romer J. Co-localization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat. Neuroendocrinology 70 (1999) 306-316
42. Woods R.P., Grafton S.T., Watson J.D., Sicotte N.L., and Mazziotta J.C. Automated image registration: II. Intersubject validation of linear and nonlinear models. J. Comput. Assist. Tomogr. 22 (1998) 153-165
43. Woods R.P., Grafton S.T., Holmes C.J., Cherry S.R., and Mazziotta J.C. Automated image registration: I. General methods and intrasubject, intramodality validation. J. Comput. Assist. Tomogr. 22 (1998) 139-152