Advertisement

Antiobesity Effects of Melanin-Concentrating Hormone Receptor 1 (MCH-R1) Antagonists

Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 209)

Abstract

Despite remarkable progress in the elucidation of energy balance and regulation, the development of new antiobesity drugs is still at the stage of infancy. This review describes the MCH and MCH receptor system with regard to its involvement in energy homeostasis and summarizes the pharmacological profiles of selected small molecule MCH-R1 antagonists that are relevant for their development as antiobesity drugs. Although their clinical value still has to be demonstrated, and challenges with regard to unwanted side effects remain to be resolved, MCH-R1 antagonists may provide an effective pharmacotherapy for the treatment of obesity in the near future.

Keywords

Melanin-concentrating hormone Obesity Energy intake Energy expenditure Pharmacotherapy 

References

  1. Abbott CR, Kennedy AR, Wren AM, Rossi M, Murphy KG, Seal LJ, Todd JF, Ghatei MA, Small CJ, Bloom SR (2003) Identification of hypothalamic nuclei involved in the orexigenic effect of melanin-concentrating hormone. Endocrinology 144:3943–3949PubMedCrossRefGoogle Scholar
  2. An S, Cutler G, Zhao JJ, Huang SG, Tian H, Li W, Liang L, Rich M, Bakleh A, Du J, Chen JL, Dai K (2001) Identification and characterization of a melanin-concentrating hormone receptor. Proc Natl Acad Sci U S A 98:7576–7581PubMedCrossRefGoogle Scholar
  3. Anand BK, Brobeck JR (1951) Localization of a feeding center in the hypothalamus of the rat. Proc Soc Exp Biol Med 77:323–324PubMedGoogle Scholar
  4. Arterburn DE, Crane PK, Veenstra DL (2004) The efficacy and safety of sibutramine for weight loss: a systemic review. Arch Intern Med 164:994–1003PubMedCrossRefGoogle Scholar
  5. Bachner D, Kreienkamp H, Weise C, Buck F, Richter D (1999) Identification of melanin concentrating hormone (MCH) as the natural ligand for the orphan somatostatin-like receptor 1 (SLC-1). FEBS Lett 457:522–524PubMedCrossRefGoogle Scholar
  6. Balavoine F, Malabre P, Alleaume T, Rey A, Cherfils V, Jeanneton O, Seigneurin VS, Revah F (2007) Design and synthesis of novel hydantoin-containing melanin concentrating hormone receptor antagonists. Bioorg Med Chem Lett 17:3754–3759PubMedCrossRefGoogle Scholar
  7. Bell CG, Meyre D, Samson C, Boyle C, Lecoeur C, Tauber M, Jouret B, Jaquet D, Levy-Marchal C, Charles MA, Weill J, Gilson F, Mein CA, Froquel P, Walley AJ (2005) Association of melanin-concentrating hormone receptor 1 5′polymorphism with early onset extreme obesity. Diabetes 54:3049–3055PubMedCrossRefGoogle Scholar
  8. Bittencourt JC, Presse F, Arias C, Peto C, Vaughan J, Nahon JL, Vale W, Sawchenko PE (1992) The melanin-concentrating hormone system of the rat brain: an immuno- and hybridization histochemical characterization. J Comp Neurol 319:218–245PubMedCrossRefGoogle Scholar
  9. Borowsky B, Durkin MM, Ogozalek K, Marzabadi MR, DeLeon J, Heurich R, Lichtblau H, Shaposhnik Z, Daniewska I, Blackburn TP, Branchek TA, Gerald C, Vaysse PJ, Forray C (2002) Antidepressant, anxiolytic and anorectic effects of a melanin concentrating hormone-1 receptor antagonist. Nat Med 8:825–830PubMedGoogle Scholar
  10. Bradley RL, Kokkotou EG, Matatos-Flier E, Cheatam B (2000) Melanin concentrating hormone (MCH) regulates leptin synthesis and secretion in rat adipocytes. Diabetes 49:1073–1077PubMedCrossRefGoogle Scholar
  11. Breton C, Schorpp M, Nahon JL (1993) Isolation and characterization of the human melanin concentrating hormone gene and a variant gene. Brain Res Mol Brain Res 18:297–310PubMedCrossRefGoogle Scholar
  12. Carpenter AJ, Hertzog DL (2002) Melanin-concentrating hormone receptor antagonists as potential antiobesity agents. Expert Opin Ther Patents 12:1639–1646CrossRefGoogle Scholar
  13. Chambers J, Ames RS, Bergsma D, Muir A, Fitzgerald LR, Hervieu G, Dytko GM, Foley JJ, Martin J, Liu WS, Park J, Ellis C, Ganguly S, Konchar S, Cluderay J, Leslie R, Wilson S, Sarau HM (1999) Melanin-concentrating hormone is the cognate ligand for the orphan G protein-coupled receptor SLC-1. Nature 400:261–265PubMedCrossRefGoogle Scholar
  14. Chaki S, Yamaguchi J, Yamada H, Thomsen W, Tran TA, Semple G, Sekiguchi Y (2005) ATC0175; an orally active melanin-concentrating hormone receptor 1 antagonist for the potential treatment of depression and anxiety. CNS Drug Rev 11:341–352PubMedCrossRefGoogle Scholar
  15. Chen Y, Hu C, Hsu CK, Zhang Q, Bi C, Asnicar M, Hsiung HM, Fox N, Slieker LJ, Yang DD, Heiman ML, Shi Y (2002) Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity. Endocrinology 143:2469–2477PubMedCrossRefGoogle Scholar
  16. Collin M, Backberg M, Onnestam K, Meister B (2002) 5-HT1A receptor immunoreactivity in hypothalamic neurons involved in body weight control. Neuroreport 13:945–951PubMedCrossRefGoogle Scholar
  17. Collins CA, Kym PR (2003) Prospects for obesity treatment: MCH receptor antagonists. Curr Opin Investig Drugs 4:386–394PubMedGoogle Scholar
  18. Della-Zuana O, Presse F, Ortola C, Duhault J, Nahon JL, Levens N (2002) Acute and chronic administration of melanin-concentrating hormone enhances food intake and body weight in Wistar and Sprague–Dawley rats. Int J Obes Relat Metab Disord 26:1289–1295PubMedCrossRefGoogle Scholar
  19. Despres JP, Golay A, Sjostrom L (2005) Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 353:2121–2134PubMedCrossRefGoogle Scholar
  20. Dyck B, Markison S, Zhao L, Tamiya J, Grey J, Rowbottom MW, Zhang M, Vickers T, Sorensen K, Norton C, Wen J, Heise CE, Saunders J, Conlon P, Madan A, Schwarz D, Goodfellow VS (2006) A thienopyridazinone-based melanin concentrating hormone receptor 1 antagonist with potent in vivo anorectic properties. J Med Chem 49:3753–3756PubMedCrossRefGoogle Scholar
  21. Elias CF, Aschkenasi C, Lee C, Kelly J, Ahima RS, Bjorbaek C, Flier JS, Saper CB, Elmquist JK (1999) Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23:775–786PubMedCrossRefGoogle Scholar
  22. Elias CF, Saper CB, Maratos-Flier E, Tritos NA, Lee C, Kelly J, Tatro JB, Hoffman GE, Ollmann MM, Barsh GS, Sakurai T, Yanagisawa M, Elmquist JK (1998) Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area. J Comp Neurol 402:442–459PubMedCrossRefGoogle Scholar
  23. Elliott JC, Harrold JA, Brodin P, Enquist K, Backman A, Bystrom M, Lindgren K, King P, Williams G (2004) Increases in melanin-concentrating hormone and MCH receptor levels in the hypothalamus of dietary-obese rat. Brain Res Mol Brain Res 128:150–159PubMedCrossRefGoogle Scholar
  24. Finer N (2002) Sibutramine: its mode of action and efficacy. Int J Obes Relat Metab Disord 26(Suppl 4):S29–S33PubMedCrossRefGoogle Scholar
  25. Fox BM, Natero R, Richard K, Connors R, Roveto PM, Beckmann H, Haller K, Golde J, Xiao SH, Kayser F (2011) Novel pyrrolidine melanin-concentrating hormone receptor 1 antagonists with reduced hERG inhibition. Bioorg Med Chem Lett 21:2460–2467PubMedCrossRefGoogle Scholar
  26. Foxcroft DR, Milne R (2000) Orlistat for the treatment of obesity: rapid review and cost effectiveness model. Obes Rev 1:121–126CrossRefGoogle Scholar
  27. Gehlert DR, Rasmussen K, Shaw J, Li X, Ardayfio P, Craft L, Coskun T, Zhang HY, Chen Y, Witkin JM (2009) Preclinical evaluation of melanin-concentrating hormone receptor 1 antagonism for the treatment of obesity and depression. J Pharmacol Exp Ther 329:429–438PubMedCrossRefGoogle Scholar
  28. Gibson WT, Pissios P, Trombly DJ, Luan J, Keogh J, Wareham NJ, Maratos-Flier E, O’Rahilly S, Farooqi IS (2004) Melanin-concentrating hormone receptor mutations and human obesity: functional analysis. Obes Res 12:743–749PubMedCrossRefGoogle Scholar
  29. Gonzalez MI, Baker BI, Hole DR, Wilson CA (1998) Behavioral effects of neuropeptide E-I(NEI) in the female rat: interaction with alpha-MSH, MCH and dopamine. Peptides 19:1007–1016PubMedCrossRefGoogle Scholar
  30. Guo T, Shao Y, Qian G, Rokosz LL, Stauffer TM, Hunter RC, Babu SD, Gu H, Hobbs DW (2005) Discovery and SAR of biaryl piperidine MCH1 receptor antagonists through solid-phase encoded combinatorial synthesis. Bioorg Med Chem Lett 15:3696–3700PubMedCrossRefGoogle Scholar
  31. Hanada R, Nakazato M, Mutsukura S, Murakami N, Yoshimatu H, Sakata T (2000) Differential regulation of MCH and orexin genes in the agouti-related protein/melanocortin-4 (AgRP/MC4) receptor system. Biochem Biophys Res Commun 268:88–91PubMedCrossRefGoogle Scholar
  32. Handlon AL, Zhou H (2006) Melanin-concentrating hormone-1 receptor antagonists for the treatment of obesity. J Med Chem 49:4017–4022PubMedCrossRefGoogle Scholar
  33. Hanif MW, Kumar S (2002) Pharmacological management of obesity. Expert Opin Pharmacother 3:1711–1718PubMedCrossRefGoogle Scholar
  34. Hawes BE, Kil E, Green B, O’Neill K, Fried S, Graziano MP (2000) The melanin concentrating hormone receptor couples to multiple G proteins to activate diverse intracellular signaling pathways. Endocrinology 141:4524–4532PubMedCrossRefGoogle Scholar
  35. Hedley AA, Ogden CL, Johnson CL, Carroll MD, Curtin LR, Flegal KM (2004) Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002. J Am Med Assoc 291:2847–2850CrossRefGoogle Scholar
  36. Hervieu G, Nahon JL (1995) Pro-melanin-concentrating hormone messenger ribonucleic acid and peptides expression in peripheral tissues of the rat. Neuroendocrinology 61:348–364PubMedCrossRefGoogle Scholar
  37. Herve C, Fellmann D (1997) Changes in rat melanin-concentrating hormone and dynorphin messenger ribonucleic acids induced by food deprivation. Neuropeptides 31:237–242PubMedCrossRefGoogle Scholar
  38. Hervieu GJ, Cluderay JE, Harrison D, Meakin J, Maycox P, Nasir S, Leslie RA (2000) The distribution of the mRNA and protein products of the melanin-concentrating hormone (MCH) receptor gene, slc-1, in the central nervous system of the rat. Eur J Neurosci 12:1194–1216PubMedCrossRefGoogle Scholar
  39. Hertzog DL, Al-Barazanji KA, Bigham EC, Bishop MJ, Britt CS, Carlton DL, Cooper JP, Daniels AJ, Garrido DM, Goetz AS, Grizzle MK, Guo YC, Handlon AL, Ignar DM, Morgan RO, Peat AJ, Tavares FX, Zhou H (2006) The discovery and optimization of pyrimidinone-containing MCH R1 antagonists. Bioorg Med Chem Lett 16:4723–4727PubMedCrossRefGoogle Scholar
  40. Hill J, Duckworth M, Murdock P, Rennie G, Sabido-David C, Ames RS, Szekeres P, Wilson S, Bergsma DJ, Gloger IS, Levy DS, Chambers JK, Muir AI (2001) Molecular cloning and functional characterization of MCH2, a novel human MCH receptor. J Biol Chem 276:20125–20129PubMedCrossRefGoogle Scholar
  41. Hu XE, Wos JA, Dowty ME, Suchanek PM, Ji W, Chambers JB, Benoit SC, Clegg DJ, Reizes O (2008) Small-molecule melanin-concentrating hormone-1 receptor antagonists require brain penetration for inhibition of food intake and reduction in body weight. J Pharmacol Exp Ther 324:206–213Google Scholar
  42. Huang Q, Viale A, Picard F, Nahon JL, Richard D (1999) Effects of leptin on Melanin-concentrating hormone (MCH) expression in the brain of lean and obese Lep(ob)/Lep(ob) mice. Neuroendocrinology 69:145–153PubMedCrossRefGoogle Scholar
  43. Huang CQ, Baker T, Schwarz D, Fan J, Heise CE, Zhang M, Goodfellow VS, Markison S, Gogas KR, Chen T, Wang XC, Zhu YF (2005) 1-(4-Amino-phenyl) pyrrolidin-3-yl-amine and 6-(3-amino-pyrrolidin-1-yl)-pyridin-3-yl-amine derivatives as melanin-concentrating hormone receptor-1 antagonists. Bioorg Med Chem Lett 15:3701–3706PubMedCrossRefGoogle Scholar
  44. Hvizdos KM, Markham A (1999) Orlistat: a review of its use in the management of obesity. Drugs 58:743–760PubMedCrossRefGoogle Scholar
  45. Ito M, Gomori A, Ishihara A, Oda Z, Mashiko S, Matsushita H, Yumoto M, Ito M, Sano H, Tokita S, Moriya M, Iwaasa H, Kanatani A (2003) Characterization of MCH-mediated obesity in mice. Am J Physiol Endocrinol Metabol 284:E940–E945Google Scholar
  46. Iyengar RR, Lynch JK, Mulhern MM, Judd AS, Freeman JC, Gao J, Souers AJ, Zhao G, Wodka D, Falls HD, Brodjian S, Dayton BD, Reilly RM, Swanson S, Su Z, Martin RL, Leitza ST, Houseman KA, Diaz G, Collins CA, Sham HL, Kym PR (2007) An evaluation of 3,4-methylenedioxy phenyl replacements in the aminopiperidine chromone class of MCHr1 antagonists. Bioorg Med Chem Lett 17:874–878PubMedCrossRefGoogle Scholar
  47. Jezova D, Bartanusz V, Westergren I, Johansson BB, Rivier J, Vale W, Rivier C (1992) Rat melanin-concentrating hormone stimulates adrenocorticotropin secretion: evidence for a site of action in brain regions protected by the blood-brain barrier. Endocrinology 130:1024–1029PubMedCrossRefGoogle Scholar
  48. Judd AS, Souers AJ, Kym PR (2008) Lead optimization of melanin concentrating hormone receptor 1 antagonists with low hERG channel activity. Curr Top Med Chem 8:1152–1157PubMedCrossRefGoogle Scholar
  49. Kawauchi H, Kawazoe I, Tsubokawa M, Kishida M, Baker BI (1983) Characterization of melanin concentrating hormone in chum salmon pituitaries. Nature 305:321–323PubMedCrossRefGoogle Scholar
  50. Kennedy AR, Todd JF, Dhillo WS, Seal LJ, Ghatei MA, O’Toole CP, Jones M, Witty D, Winborne K, Riley G, Hervieu G, Wilson S, Bloom SR (2003) Effects of direct injection of melanin-concentrating hormone into the paraventricular nucleus: further evidence for a stimulatory role in the adrenal axis via SLC-1. J Neuroendocrinol 15:268–272PubMedCrossRefGoogle Scholar
  51. Knigge KM, Wagner JE (1997) Melanin-concentrating hormone (MCH) involvement in pentylenetetrazole (PTZ)-induced seizure in rat and guinea pig. Peptides 18:1095–1097PubMedCrossRefGoogle Scholar
  52. Kokkotou EG, Tritos NA, Mastaitis JW, Slieker L, Maratos-Flier E (2001) Melanin concentrating hormone receptor is a target of leptin action in the mouse brain. Endocrinology 142:680–686PubMedCrossRefGoogle Scholar
  53. Kopelman PG (2000) Obesity as a medical problem. Nature 404:635–643PubMedGoogle Scholar
  54. Kowalski TJ, Mcbriar MD (2004) Therapeutic potential of melanin-concentrating hormone-1 receptor antagonists for the treatment of obesity. Expert Opin Investig Drugs 13:1113–1122PubMedCrossRefGoogle Scholar
  55. Kym PR, Iyengar R, Souers AJ, Lynch JK, Judd AS, Gao J, Freeman J, Mulhern M, Zhao G, Vasudevan A, Wodka D, Blackburn C, Brown J, Che JL, Cullis C, Lai SJ, LaMarche MJ, Marsilje T, Roses J, Sells T, Geddes B, Govek E, Patane M, Fry D, Dayton BD, Brodjian S, Falls D, Brune M, Bush E, Shapiro R, Knourek-Segel V, Fey T, McDowell C, Reinhart GA, Preusser LC, Marsh K, Hernandez L, Sham HL, Collins CA (2005) Discovery and characterization of aminopiperidinecoumarin melanin concentrating hormone receptor 1 antagonists. J Med Chem 48:5888–5891PubMedCrossRefGoogle Scholar
  56. Lembo PM, Grazzini E, Cao J, Hubatsch DA, Pelletier M, Hoffert C, St-Onge S, Pou C, Labrecque J, Groblewski T, O'Donnell D, Payza K, Ahmad S, Walker P (1999) The receptor for the orexigenic peptide melanin-concentrating hormone is a G protein-coupled receptor. Nat Cell Biol 1:267–271PubMedCrossRefGoogle Scholar
  57. Lucki I (1997) The forced swimming test as a model for core and component behavioral effects of antidepressant drugs. Behav Pharmacol 8:523–532PubMedCrossRefGoogle Scholar
  58. Ludwig DS, Tritos NA, Mastaitis JW, Kulkarni R, Kokkotou E, Elmquist J, Lowell B, Flier JS, Maratos-Flier E (2001) Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance. J Clin Invest 107:379–386PubMedCrossRefGoogle Scholar
  59. Luthin DR (2007) Anti-obesity effects of small molecule melanin-concentrating hormone receptor1 (MCHR1) antagonists. Life Sci 81:423–440PubMedCrossRefGoogle Scholar
  60. Lynch JK, Collins CA, Freeman JC, Gao J, Iyengar RR, Judd AS, Kym PR, Mulhern MM, Sham HL, Souers AJ, Zhao G, Wodka D (2005) Preparation of piperidinyl chromenecarboxamides as antagonists of melanin concentrating hormone effects on the melanin concentrating hormone receptor. US 2005/209274Google Scholar
  61. Macdonald D, Mugolo N, Zhang R, Durkin JP, Yao X, Strader CD, Graziano MP (2000) Molecular characterization of the melanin-concentrating hormone/receptor complex: identification of critical residues involved in binding and activation. Mol Pharmacol 58:217–225PubMedGoogle Scholar
  62. Marsh DJ, Weingarth DT, Novi DE, Chen HY, Trumbauer ME, Chen ASM, Guan XM, Jiang MM, Feng Y, Camacho RE, Shen Z, Frazier EG, Yu H, Metzger JM, Kuca SJ, Shearman LP, Gopal-Truter S, MacNeil DJ, Strack AM, MacIntyre DE, Van der Ploeg LH, Qian S (2002) Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. Proc Natl Acad Sci U S A 99:3240–3245PubMedCrossRefGoogle Scholar
  63. McBride RB, Beckwith BE, Swenson RR, Sawyer TK, Hadley ME, Matsunaga TO, Hruby VJ (1994) The actions of melanin-concentrating hormone (MCH) on passive avoidance in rats: a preliminary study. Peptides 15:757–759PubMedCrossRefGoogle Scholar
  64. McBriar MD (2007) Melanin concentrating hormone receptor antagonists as antiobesity agents: from M2 to MCHR-1. Curr Top Med Chem 7:1440–1454PubMedCrossRefGoogle Scholar
  65. McBriar MD, Guzik H, Shapiro S, Paruchova J, Xu R, Palani A, Clader JW, Cox K, Greenlee WJ, Hawes BE, Kowalski TJ, O’Neill K, Spar BD, Weig B, Weston DJ, Farley C, Cook J (2006) Discovery of orally efficacious melanin-concentrating hormone receptor-1 antagonists as antiobesity agents. Synthesis, SAR, and biological evaluation of bicyclo[3.1.0]hexyl ureas. J Med Chem 49:2294–2310PubMedCrossRefGoogle Scholar
  66. McNeely W, Goa KL (1998) Sibutramine: a review of its contribution to the management of obesity. Drugs 56:1093–1124CrossRefGoogle Scholar
  67. Mendez-Andino JL, Wos JA (2007) MCH-R1 antagonists: what is keeping most research programs away from the clinic? Drug Discov Today 12:972–979PubMedCrossRefGoogle Scholar
  68. Miller CL, Hruby VJ, Matsunaga TO, Bickford PC (1993) Alpha-MSH and MCH are functional antagonists in a Central nervous system (CNS) auditory gating paradigm. Ann NY Acad Sci 680:571–574PubMedCrossRefGoogle Scholar
  69. Mori M, Harada M, Terao Y, Sugo T, Watanabe T, Shimomura Y, Abe M, Shintani Y, Onda H, Nishimura O, Fujino M (2001) Cloning of a novel G protein-coupled receptor, SLT, a subtype of the melanin-concentrating hormone receptor. Biochem Biophys Res Commun 283:1013–1018PubMedCrossRefGoogle Scholar
  70. Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM (2006) Prevalence of overweight and obesity in the United States, 1999–2004. J Am Med Assoc 295:1549–1555CrossRefGoogle Scholar
  71. Pereira-da-Silva M, Torsoni MA, Nourani HV, Augusto VD, Souza CT, Gasparetti AL, Carvalheira JB, Ventrucci G, Marcondes MC, Cruz-Neto AP, Saad MJ, Boschero AC, Carneiro EM, Velloso LA (2003) Hypothalamic melanin-concentrating hormone is Induced by cold exposure and participates in the control of energy expenditure in rats. Endocrinology 144:4831–4840PubMedCrossRefGoogle Scholar
  72. Pissios P, Bradley RL, Maratos-Flier E (2006) Expanding the scales: the multiple roles of MCH in regulating energy balance and other biological functions. Endocr Rev 27:606–620PubMedCrossRefGoogle Scholar
  73. Presse F, Nahon JL, Fischer WH, Vale W (1990) Structure of the human melanin concentrating hormone mRNA. Mol Endocrinol 4:632–637PubMedCrossRefGoogle Scholar
  74. Presse F, Hervieu G, Imaki T, Sawchenko PE, Vale W, Nahon JL (1992) Rat melanin-concentrating hormone messenger ribonucleic acid expression: marked changes during development and after stress and glucocorticoid stimuli. Endocrinology 131:1241–1250PubMedCrossRefGoogle Scholar
  75. Qu D, Ludwig DS, Gammeltoft S, Piper M, Pelleymounter MA, Cullen MJ, Mathes WF, Przypek R, Kanarek R, Maratos-Flier E (1996) A role for melanin-concentrating hormone in the central regulation of feeding behavior. Nature 380:243–247PubMedCrossRefGoogle Scholar
  76. Rivera G, Bocanegra-Garcia V, Galiano S, Cirauqui N, Ceras J, Pérez S, Aldana I, Monge A (2008) Melanin-concentrating hormone receptor 1 antagonists: a new perspective for the pharmacologic treatment of obesity. Curr Med Chem 15:1025–1043PubMedCrossRefGoogle Scholar
  77. Rodriguez M, Beauverger P, Naime I, Rique H, Ouvry C, Souchaud S, Dromaint S, Nagel N, Suply T, Audinot V, Boutin JA, Galizzi JP (2001) Cloning and molecular characterization of the novel human melanin-concentrating hormone receptor MCH2. Mol Pharmacol 60:632–639PubMedGoogle Scholar
  78. Rokosz LL (2007) Discovery and development of melanin-concentrating hormone receptor 1 antagonists for the treatment of obesity. Expert Opin Drug Discov 2:1301–1327CrossRefGoogle Scholar
  79. Rossi M, Beak SA, Choi SJ, Small CJ, Morgan DG, Ghatei MA, Smith DM, Bloom SR (1999) Investigation of the feeding effects of melanin concentrating hormone on food intake-action independent of galanin and the melanocortin receptors. Brain Res 846:164–170PubMedCrossRefGoogle Scholar
  80. Rovere C, Viale A, Nahon JL, Kitabgi P (1996) Impaired processing of brain pro-neurotensin and pro-melanin-concentrating hormone in obese fat/fat mice. Endocrinology 137:2954–2958PubMedCrossRefGoogle Scholar
  81. Sahu A (1998) Leptin decreases food intake induced by melanin-concentrating hormone (MCH), galanin (GAL) and neuropeptide Y (NPY) in the rat. Endocrinology 139:4739–4742PubMedCrossRefGoogle Scholar
  82. Sailer AW, Sano H, Zeng Z, McDonald TP, Pan J, Pong SS, Feighner SD, Tan CP, Fukami T, Iwaasa H, Hreniuk DL, Morin NR, Sadowski SJ, Ito M, Bansal A, Ky B, Figueroa DJ, Jiang Q, Austin CP, MacNeil DJ, Ishihara A, Ihara M, Kanatani A, Vander Ploeg LH, Howard AD, Liu Q (2001) Identification and characterization of a second melanin-concentrating hormone receptor, MCH-2R. Proc Natl Acad Sci U S A 98:7564–7569PubMedCrossRefGoogle Scholar
  83. Saito Y, Nothacker HP, Wang Z, Lin SH, Leslie F, Civelli O (1999) Molecular characterization of the melanin-concentrating hormone receptor. Nature 400:265–269PubMedCrossRefGoogle Scholar
  84. Sasikumar TK, Qiang L, Burnett DA, Greenlee WJ, Hawes BE, Kowalski TJ, O'Neill K, Spar BD, Weig B (2006) Novel aminobenzimidazoles as selective MCH-R1 antagonists for the treatment of metabolic diseases. Bioorg Med Chem Lett 16:5427–5431PubMedCrossRefGoogle Scholar
  85. Semple G (2004) Identification and biological activity of a new series of antagonists of hMCH-R1. Presented at the 228th National American Chemical Society Meeting, Philadelphia, PA, August 22, Medi 007Google Scholar
  86. Shimada M, Tritos NA, Lowell BB, Flier JS, Maratos-Flier E (1998) Mice lacking melanin concentrating hormone are hypophagic and lean. Nature 396:670–674PubMedCrossRefGoogle Scholar
  87. Shimomura Y, Mori M, Sugo T, Ishibashi Y, Abe M, Kurokawa T, Onda H, Nishimura O, Sumino Y, Fujino M (1999) Isolation and identification of melanin-concentrating hormone as the endogenous ligand of the SLC-1 receptor. Biochem Biophys Res Commun 261:622–626PubMedCrossRefGoogle Scholar
  88. Skofitsch G, Jacobowitz DM, Zamir N (1985) Immunohistochemical localization of a melanin concentrating hormone-like peptide in the rat brain. Brain Res Bull 15:635–649PubMedCrossRefGoogle Scholar
  89. Smith DG, Davis RJ, Rorick-Kehn L, Morin M, Witkin JM, McKinzie DL, Nomikos GG, Gehlert DR (2006) Melanin-concentrating hormone-1 receptor modulates neuroendocrine, behavioral, and corticolimbic neurochemical stress responses in mice. Neuropsychopharmacol 31:1135–1145CrossRefGoogle Scholar
  90. Souers AJ, Gao J, Wodka D, Judd AS, Mulhern MM, Napier JJ, Brune ME, Bush EN, Brodjian SJ, Dayton BD, Shapiro R, Hernandez LE, Marsh KC, Sham HL, Collins CA, Kym PR (2005) Synthesis and evaluation of urea-based indazoles as melanin concentrating hormone receptor 1 antagonists for the treatment of obesity. Bioorg Med Chem Lett 15:2752–2757PubMedCrossRefGoogle Scholar
  91. Souers AJ, Iyengar RR, Judd AS, Beno DW, Gao J, Zhao G, Brune ME, Napier JJ, Mulhern MM, Lynch JK, Freeman JC, Wodka D, Chen CJ, Falls HD, Brodjian S, Dayton BD, Diaz GJ, Bush EN, Shapiro R, Droz BA, Knourek-Segel V, Hernandez LE, Marsh KC, Reilly RM, Sham HL, Collins CA, Kym PR (2007) Constrained 7-fluorocarboxychromone-4-aminopiperidine based melanin concentrating hormone receptor 1 antagonists: the effects of chirality on substituted indan 1-ylamines. Bioorg Med Chem Lett 17:884–889PubMedCrossRefGoogle Scholar
  92. Staten MA (2007) Challenges in the discovery and development of new agents for the treatment of obesity. Clin Pharmacol Ther 81:753–755PubMedCrossRefGoogle Scholar
  93. Stricker-Krongrad A, Dimitrov T, Beck B (2001) Central and peripheral dysregulation of melanin concentrating hormone in obese Zucker rats. Brain Res Mol Brain Res 92:43–48PubMedCrossRefGoogle Scholar
  94. Tadayyon M, Welters HJ, Haynes AC, Cluderay JE, Hervieu G (2000) Expression of melanin concentrating hormone receptors in insulin-producing cells: MCH stimulates insulin release in RINm5F and CRI-G1 cell lines. Biochem Biophys Res Commun 275:709–712PubMedCrossRefGoogle Scholar
  95. Takekawa S, Asami A, Ishihara Y, Terauchi J, Kato K, Shimomura Y, Mori M, Murakoshi H, Kato K, Suzuki N, Nishimura O, Fujino M (2002) T-226296: a novel, orally active and selective melanin-concentrating hormone receptor antagonist. Eur J Pharmacol 438:129–135PubMedCrossRefGoogle Scholar
  96. Tan CP, Sano H, Iwaasa H, Pan J, Sailer AW, Hreniuk DL, Feighner SD, Palyha OC, Pong SS, Figueroa DJ, Austin CP, Jiang MM, Yu H, Ito J, Ito M, Guan XM, MacNeil DJ, Kanatani A, Van der Ploeg LHT, Howard AD (2002) Melanin-concentrating hormone receptor subtypes 1 and 2: species-specific gene expression. Genomics 79:785–792PubMedCrossRefGoogle Scholar
  97. Tavares FX, Al-Barazanji KA, Bigham EC, Bishop MJ, Britt CS, Carlton DL, Feldman PL, Goetz AS, Grizzle MK, Guo YC, Handlon AL, Hertzog DL, Ignar DM, Lang DG, Ott RJ, Peat AJ, Zhou HQ (2006a) Potent, selective, and orally efficacious antagonists of melanin-concentrating hormone receptor 1. J Med Chem 49:7095–7107PubMedCrossRefGoogle Scholar
  98. Tavares FX, Al-Barazanji KA, Bishop MJ, Britt CS, Carlton DL, Cooper JP, Feldman PL, Garrido DM, Goetz AS, Grizzle MK, Hertzog L, Ignar DM, Lang DG, McIntyre MS, Ott RJ, Peat AJ, Zhou HQ (2006b) 6-(4-Chlorophenyl)-3-substituted-thieno[3,2-d]pyrimidin-4(3H)-one-based melanin concentrating hormone receptor 1 antagonist. J Med Chem 49:7108–7118PubMedCrossRefGoogle Scholar
  99. Tritos NA, Elmquist JK, Mastaitis JW, Flier JS, Maratos-Flier E (1998) Characterization of expression of hypothalamic appetite-regulating peptides in obese hyperleptinemic brown adipose tissue-deficient (uncoupling protein-promoter-driven diphtheria toxin A) mice. Endocrinology 139:4634–4641PubMedCrossRefGoogle Scholar
  100. Varas MM, Perez MF, Ramirez OA, de Barioglio SR (2003) Increased susceptibility to LTP generation and changes in NMDA-NR1 and NR-2B subunits mRNA expression in rat hippocampus after MCH administration. Peptides 24:1403–1411PubMedCrossRefGoogle Scholar
  101. Vasudevan A, Souers AJ, Freeman JC, Verzal MK, Gao J, Mulhern MM, Wodka D, Lynch JK, Engstrom KM, Wagaw SH, Brodjian S, Dayton B, Falls DH, Bush E, Brune M, Shapiro RD, Marsh KC, Hernandez LE, Collins CA, Kym PR (2005) Aminopiperidine indazoles as orally efficacious melanin concentrating hormone receptor-1 antagonists. Bioorg Med Chem Lett 15:5293–5297PubMedCrossRefGoogle Scholar
  102. Vaughan JM, Fischer WH, Hoeger C, Rivier J, Vale W (1989) Characterization of melanin concentrating hormone from rat hypothalamus. Endocrinology 125:1660–1665PubMedCrossRefGoogle Scholar
  103. Viale A, Zhixing Y, Breton C, Pedeutour F, Coquerel A, Jordan D, Nahon JL (1997) The melanin-concentrating hormone gene in human: flanking region analysis, fine chromosome mapping, and tissue-specific expression. Brain Res Mol Brain Res 46:243–255PubMedCrossRefGoogle Scholar
  104. Wang S, Behan J, O’Neill K, Weig B, Fried S, Laz T, Bayne M, Gustafson E, Hawes BE (2001) Identification and pharmacological characterization of a novel human melanin concentrating hormone receptor, MCH-R2. J Biol Chem 276:34664–34670PubMedCrossRefGoogle Scholar
  105. Wermter AK, Reichwald K, Buch T, Geller F, Platzer C, Huse K, Hess C, Remschmidt H, Gudermann T, Preibisch G, Siegfried W, Goldschmidt HP, Li WO, Price RA, Biebermann H, Krude H, Vollmert C, Wichmann HE, Illig T, Sorensen TI, Astrup A, Larsen LH, Pedersen O, Eberle D, Clement K, Blundell J, Wabitsch M, Schafer H, Platzer M, Hinney A, Hebebrand J (2005) Mutation analysis of the MCHR1 gene in human obesity. Eur J Endocrinol 152:851–862PubMedCrossRefGoogle Scholar
  106. Wu WL, Burnett DA, Caplen MA, Domalski MS, Bennett C, Greenlee WJ, Hawes BE, O’Neill K, Weig B, Weston D, Spar B, Kowalski T (2006) Design and synthesis of orally efficacious benzimidazoles as melanin-concentrating hormone receptor 1 antagonists. Bioorg Med Chem Lett 16:3674–3678PubMedCrossRefGoogle Scholar
  107. Zhang, P, Liand, JD, Samdusky, GE (1999) Hypothalamic MCH mRNA and protein are increased in human obesity. Satellite Symposium; 9th International Congress of Obesity France, Proceedings of the Symposium. Int J Obes, p 51Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Department of Pharmacology and Pharmaceutical SciencesGachon University of Medicine and ScienceIncheonRepublic of Korea

Personalised recommendations