Recent advances in the discovery of melanin-concentrating hormone receptor antagonists

Current Opinion in Drug Discovery and Development

Volumn 9, Issue 4, 2006, Pages 496-508

  McBriar, Mark D ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Antidepressant; Anxiolytic; G protein coupled receptor; Melanin concentrating hormone; Melanin concentrating hormone receptor antagonist; Obesity

Indexed keywords

A 761; A 798; AMG 076; AMIDOPIPERIDINE DERIVATIVE; AMINOQUINAZOLINE DERIVATIVE; ANTIDEPRESSANT AGENT; AR 129330; ATC 0065; ATC 0175; BENZAMIDE DERIVATIVE; BENZODIAZEPINE DERIVATIVE; CATECHOL DERIVATIVE; COUMARIN DERIVATIVE; FLUOXETINE; GW 3430; HORMONE RECEPTOR; HORMONE RECEPTOR BLOCKING AGENT; INDAZOLE DERIVATIVE; MELANIN CONCENTRATING HORMONE; MELANIN CONCENTRATING HORMONE 1 RECEPTOR; MELANIN CONCENTRATING HORMONE 1 RECEPTOR ANTAGONIST; MELANIN CONCENTRATING HORMONE 2 RECEPTOR; N (3,3 DIMETHYL 6 INDOLINYL) 2 (4 PYRIDINYLMETHYLAMINO)NICOTINAMIDE; N (6 DIMETHYLAMINOMETHYL 5,6,7,8 TETRAHYDRO 2 NAPHTHYL) 4' FLUORO 1,1' BIPHENYL 4 CARBOXAMIDE; NICOTINAMIDE DERIVATIVE; SIBUTRAMINE; SNAP 7941; SNAP 94847; SULFONAMIDE; UNCLASSIFIED DRUG; UNINDEXED DRUG; UREA DERIVATIVE;

ANXIETY DISORDER; AREA UNDER THE CURVE; BEHAVIOR; CLINICAL TRIAL; COMORBIDITY; DEPRESSION; DRUG BIOAVAILABILITY; DRUG DOSE REGIMEN; DRUG EFFECT; DRUG EFFICACY; DRUG HALF LIFE; DRUG STRUCTURE; ENERGY BALANCE; HUMAN; MUTAGENIC ACTIVITY; NONHUMAN; OBESITY; REVIEW; STRUCTURE ACTIVITY RELATION; TRANQUILIZING ACTIVITY; WEIGHT REDUCTION;

ANIMALS; HUMANS; OBESITY; RECEPTORS, PITUITARY HORMONE; TECHNOLOGY, PHARMACEUTICAL;

EID: 33746126228     PISSN: 13676733     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (69)

1. Downey M: Statement of the American Obesity Association before the Committee on Government Reform, House of Representatives. American Obesity Association, Washington, DC, USA (2004). http://obesity1.tempdomainname.com/ subs/advocacy/GovtReform2004. shtml
2. Blackburn GL, Walker WA: Science-based solutions to obesity: What are the roles of academia, government, industry and health care? Am J Clin Nutr (2005) 82(1 Suppl):207S-210S.
3. Flegal KM, Carroll MD, Ogden CL, Johnson CL: Prevalence and trends in obesity among US adults, 1999-2000. J Am Med Assoc (2002) 288(14):1723-1727.
4. Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP: The continuing epidemics of obesity and diabetes in the United States. J Am Med Assoc (2001)286(10):1195-1200.
5. Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS: Prevalence of obesity, diabetes and obesity-related health risk factors, 2001. J Am Med Assoc (2003) 289(1):76-79.
6. Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz WH: The disease burden associated with overweight and obesity. J Am Med Assoc (1999) 282(16):1523-1529.
7. Wilson PW, Kannel WB, Silbershatz H, D'Agostino RB: Clustering of metabolic factors and coronary heart disease. Arch Intern Med (1999)159(10):1104-1109.
8. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, llanne-Parikka P, Keinanen-Kiukaanniemi S, Laasko M, Louheranta A, Rastas M, Salminen V et at. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. New Engl J Med (2001) 344(18):1343-1350.
9. Corey-Lisle PK, Nash R, Stang P, Swindle R: Response, partial response and nonresponse in primary care treatment of depression. Arch Intern Med (2004) 164(11):1197-1204.
10. Pacher P, Kecskemeti V: Trends in the development of new antidepressants. Is there a light at the end of the tunnel? Curr Med Chem (2004) 11(7):925-943.
11. Dyke HJ, Ray NC: Recent developments in the discovery of MCH-1R antagonists for the treatment of obesity - an update. Expert Opin Ther Patents (2005) 15(10):1303-1313. Reviews recent patenting activity related to the discovery of small-molecule MCH-1R antagonists.
12. Nahon JL, Presse F, Bittencourt JC, Sawchenko PE, Vale W: The rat melanin-concentrating hormone messenger ribonucleic acid encodes multiple putative neuropeptldes coexpressed in the dorsolateral hypothalamus. Endocrinology (1989) 125(4):2056-2065.
13. Viale A, Zhixing Y, Breton C, Pedeutour F, Coquerel A, Jordan D, Nahon JL: The melanin-concentrating hormone gene in human: Flanking region analysis, fine chromosome mapping and tissue-specific expression. Brain Res Mol Brain Res (1997) 46(1-2):243-245.
14. Bittencourt JC, Presse F, Arias C, Peto C, Vaughan J, Nahon JL, Vale W, Sawchenko PE: The melanin-concentrating hormone system of the rat brain: An immuno- and hybridization histochemical characterization. J Comp Neurol (1992) 319(2):218-245.
15. 125I]-SSSOST: A new and highly potent radioligand for the melanin-concentrating hormone receptor. Br J Pharmacol (2001) 133(3):371-378.
16. Morens C, Norregaard P, Receveur J-M, van Dijk G, Scheurink AJ: Effects of MCH and a MCH1-receptor antagonist of (palatable) food and water intake. Brain Res (2005) 1062(1-2):32-38.
17. Ito M, Gomori A, lshihara A, Oda Z, Mashiko S, Matsushita H, Umoto M, Sano H, Tokita S, Moriya M, Iwaasa H et al: Characterization of MCH-mediated obesity in mice. Am J Physiol Endocrinol Metab (2003) 284(5):E940-E945
18. Ludwig DS, Tritos NA, Mastaitis JW, Kulkami R, Kokkotou E, Elmquist J, Lowell B, Flier JS, Maratos-Flier E: Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance. J Clin Invest (2001) 107(3):379-386. Confirms and provides further pharmacological evidence demonstrating that chronic central MCH signaling promotes obesity and insulin resistance in mice.
19. Kokkotou E, Jeon JY, Wang X, Marino FE, Cartson M, Trombly DJ, Maratos-Flier E: Mice with MCH ablation resist diet-Induced obesity through strain-specific mechanisms. Am J Physiol Regul Inter Comp Physiol (2005) 289(1):R117-R124.
20. An S, Cutler G, Zhao JJ, Huang SG, Tian H, Li W, bang L, Rich M, Bakleh A, Du J, Chen JL et al. Identification and characterization of a melanin-concentrating hormone receptor. Proc Natl Acad Sci USA (2001) 98(13)7576-7581.
21. Chambers J, Ames RS, Bergsma D, Muir A, Fitzgerald LR, Hervieu G, Dytko GM, Foley JJ, Martin J, Liu WS, Park J et al: Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1. Nature (1999) 400(6741):261-265. One of the first reports, along with reference [23], to describe the MCH-1R.
22. Sailer AW, Sano H, Zeng Z, McDonald TP, Pan J, Pong SS, Ferghner SD, Tan CP, Fukami T, Iwaasa H, Hreniuk DL et al: Identification and characterization of a second melanin-concentrating hormone receptor, MCH-2R. Proc Natl Acad Sci USA (2001) 98(13):7564-7569.
23. Saito Y, Nothacker HP, Wang Z, Lin SH, Leslie F, Civelli O: Molecular characterization of the melanin-concentrating-hormone receptor. Nature (1999) 400(6741):265-269. One of the first reports, along with reference [21], to describe the MCH-1R.
24. Marsh DJ, Weingarth DT, Novi DE, Chen HY, Trumbauer ME, Chen AS, Guan XM, Jiang MM, Feng Y, Camacho RE, Shen Z et al: Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. Proc Natl Acad Sci USA (2002) 99(5):3240-3245.
25. Mashiko S, Ishihara A, Gomori A, Moriya R, Ito M, Iwaasa H, Matsuda M, Feng Y, Shen Z, Marsh DJ, Bednarek MA et al: Antiobeslty effect of a melanin-concentrating hormone 1 receptor antagonist in diet-induced obese mice. Endocrinology (2005) 146(7):3080-3086.
26. Kennedy AR, Todd JF, Dhillo WS, Seal LJ, Ghatei MA, O'Toole CP, Jones M, Witty D, Winbome K, Riley G, Hervieu G et al. Effect 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 (2003) 15(3):268-272.
27. Gonzalez MI, Vaziri S, Wilson CA: Behavioral effects of α-MSH and MCH after central administration in the female rat. Peptides (1996) 17(1):171-177.
28. Georgescu D, Sears RM, Hommel JD, Barrot M, Bolanos CA, Marsh DJ, Bednarek MA, Bibb JA, Maratos-Flier E, Nestler EJ, DiLeone RJ: The hypothalamic neuropeptide melanin-concentrating hormone acts in the nucleus accumbens to modulate feeding behavior and forced-swim performance. J Neurosci (2005) 25(11):2933-2940.
29. Hervieu GJ, Cluderay JE, Harrison D, Meakin J, Maycox P, Nasir S, Leslie RA: The distribution of mRNA and protein products of the melanin-concentrating hormone (MCH) receptor gene, slc-f, in the central nervous system of the rat. Eur J Neurosci (2000) 12(4):1194-1216.
30. Smith DG, Tzavara ET, Shaw J, Luecke S, Wade M, Davis R, Salhoff C, Nomikos GG, Gehlert DR: Mesolimbic dopamine super-sensitivity in melanin-concentrating hormone-1 receptor-deficient mice. J Neurosci (2005) 25(4):914-922.
31. Ressler KJ, Nermeroff CB: Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety (2000) 12(Suppl 1):2-19.
32. Roy M, David NK, Danao JV, Baribault H, Tian H, Giogetti M: Genetic inactivation of melanin-concentrating hormone receptor subtype 1 (MCHR1) in mice exerts anxiolytic-like behavioral effects. Neuropshcyopharmacology (2006) 31(1):112-120.
33. Roy M, David N, Tian H, Giorgetti M: Genetic inactivation of melanin-concentrating hormone receptor 1 (MCHR1) in mice exerts anxiolytic and antidepressant-like effects. 34th Society for Neuroscience Meeting, San Diego, CA, USA (2004):Abs 356.3.
34. Tan CP, Sano H, Iwaasa H, Pan J, Sailer AW, Hreniuk DL, Feighner SD, Palyha OC, Pong SS, Figueroa DJ, Austin CP et al: Melanin-concentrating hormone receptor subtypes 1 and 2: Species-specific gene expression. Genomics (2002) 79(6):785-792. Describes the species-specific expression of MCH-ZR, emphasizing the importance of animal models in the drug development process.
35. Takekawa S, Asami A, Ishihara Y, Terauchi J, Kato K, Shimomura Y, Mori M, Murakoshi H, Suzuki N, Nishimura O, Fujino M: T-226296: A novel, orally active and selective melanin-concentrating hormone receptor antagonist Eur J Pharmacol (2002) 438(3):129-135. Reports the first study into oral efficacy of a low-molecular-weight MCH-1R antagonist using a pharmacodynamic feeding model.
36. Borowsky B, Durkin MM, Ogozalek K, Marzabadi MR, DeLeon J, Lagu B, Heurich R, Lichtblau H, Shaposhnik Z, Daniewska I, Blackburn TP et al. Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist Nat Med (2002) 8(8):825-830. Provides the first description of an efficacious low-molecular-weight MCH-1R antagonist using a rodent obesity model. Efficacy in rodent models of anxiety and depression are also reported.
37. IDdb Drug Report: MCH-1 receptor antagonists, Lundbeck. Thomson Scientific, London, UK (2006). http:/www.iddb.com/iddb3/iddb3_2/reports.display? id=39571&template=Drug&i_query_id=6894611
38. IDdb Drug Report: 856464. Thomson Scientific, London, UK (2006). http://www.iddb.com/iddb3/iddb3_2/reports.display?id=41401&template= Drug&i_query_id=6922076 Describes an orally active MCH-1R antagonist currently in phase I clinical trials, and reports the first achievement of subchronic efficacy with an MCH-1R antagonist.
39. Handlon AL, Al-Barazanji KA, Barvian KK, Bighan EC, Cartton DL, Carpenter AJ, Cooper JP, Daniels AJ, Garrison DT, Goetz AS, Green GM er al. Discovery of potent and selective MCH receptor-1 antagonists for the treatment of obesity. 228th American Chemical Society National Meeting, Philadelphia, PA, USA (2004):MEDI 193. Describes an orally active MCH-1R antagonist in clinical trials and presents a pharmacophore for MCH-1R antagonists.
40. Clark DE, Higgs C, Wren SP, Dyke HJ, Wong M, Norman D, Lockey PM, Roach AG: A virtual screening approach to finding novel and potent antagonists at the melanin-concentrating hormone 1 receptor. J MedChem (2004) 47(16):3962-3971. Describes the first in silico derivation of a pharmacophore for MCH-1R antagonists.
41. Ulven T, Frimurer TM, Receveur JM, Little PB, Rist O, Norregaard PK, Hogberg T: 6-Acylamino-2-aminoquinolines as potent melanin-concentrating hormone 1 receptor antagonists. Identification, structure-activity relationship and investigation of binding mode. J Med Chem (2005) 48(18):5684-5697.
42. Smith DG, Davis FU, Rorick-Kehn L, Morin M, Witkin JM, McKinzie DL, Nomikos GG, Gehlert DR: Melanin-concentrating hormone-1 receptor modulates neuroendocrine, behavioral and corticolimbic neurochemical stress responses in mice. Neuropsychopharmacology (2006) 31(6):1135-45.
43. IDdb Drug Report: AMG-076. Thomson Scientific, London, UK (2006). http://www.iddb.com/iddb3/iddb3_2/reports.display?id=48362&template =Drug&i_query_id=6922136 Describes an orally active MCH-1R antagonist in clinical trials.
44. Palani A, Shapiro S, McBriar MD, Clader JW, Greenlee WJ. Spar B, Kowalski TJ, Parley C, Cook J, van Heek M, Weig B et al. Biaryl ureas as potent and orally efficacious melanin concentrating hormone receptor 1 antagonists for the treatment of obesity. J Med Chem (2005) 48(15):4746-4749.
45. McBriar MD, Guzik H, Xu R, Paruchova J, Li S, Palani A, Clader JW, Greenlee WJ, Hawes BE, Kowalski TJ, O'Neill K et al: Discovery of bicycloalkyl urea melanin concentrating hormone receptor antagonists: Orally efficacious antiobesity therapeutics. J Med Chem (2005) 48(7):2274-2277.
46. Xu R, U S, Paruchova J, McBriar MD, Guzik H, Palani A, Clader JW, Cox K, Greenlee WJ, Hawes BE, Kowalski TJ et al. Bicyclic[4.1.0]heptanes as phenyl replacements for melanin concentrating hormone receptor antagonists. Bfoorg Med Chem (2006) 14(10):3285-3299.
47. McBriar MD, Guzik H, Shapiro S, Paruchova J, Xu R, Palani A, Clader JW, Cox K, Greenlee WJ, Hawes BE, Kowalski TJ et al. 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 (2006) 49(7):2294-2310.
48. Kowalski TJ, Spar BD, Weig B, Farley C, Cook J, Gao J, Henry M, Ghibaudi L, Fried S, O'Neill K, Del Vecchio R et at. Effects of a selective melanin-concentrating hormone 1 receptor antagonist on food intake and energy homeostasis in diet-induced obese mice. Eur J Pharm (2006) 535(1-3):182-191. Documents the pharmacological effects of chronic oral administration of an MCH-1R antagonist.
49. Kym PR, Iyengar R, Souers AJ, Lynch JK, Judd AS, Gao J, Freeman J, Mulhem M, Zhao G, Vasudevan A, Wodka D et at. Discovery and characterization of aminopiperidlnecoumarin melanin concentrating hormone receptor 1 antagonists. J Med Chem (2005) 48(19):5888-5891.
50. Iyengar R, Souers AJ, Lynch JK, Judd AS, Gao J, Freeman JC, Mulhern M, Vasudevan A, Wodka D, Blackburn C, Brown J er al: Discovery, lead optimization and in vivo studies on coumarin-based small molecule MCH-1R antagonists. 230th American Chemical Society National Meeting, Washington, DC, USA (2005):MEDI-086.
51. Mulhem M, Judd AS, Freeman JC, Lynch JK, Iyengar R, Souers AJ, Gao J, Zhao G, Wodka D, Diaz G, Martin R et al. Identification and SAR of HERG selective melanin-concentrating hormone receptor 1 antagonists. 230th American Chemical Society National Meeting, Washington, DC, USA (2005):MEDI-087.
52. Freeman JC, Lynch JK, Mulhem MM, Judd AS, Iyengar RR, Zhao G, Brodjian S, Falls D, Dayton BD, Ogiela CA, Sidorowicz HE et al: 4-Oxo-4H-chromene-2- carboxamides as melanin-concentrating hormone antagonists: Structure-activity relationship of antiobesity therapeutics. 230th American Chemical Society National Meeting, Washington, DC, USA (2005):MEDI-085.
53. Souers AJ, Polakowski JS, Campbell TJ Jr, Segreti JA, Freeman JC, Gao J, lyengar R, Judd AS, Lynch JK, Mulhern MM, Vasudevan A et al: Implementation of an anesthetized rat cardiovascular safety model as a SAR tool to guide triaging of novel MCHR1 antagonists. 230th American Chemical Society National Meeting, Washington, DC, USA (2005):MEDI-470.
54. Souers AJ, Gao J, Brune M, Bush E, Wodka D, Vasudevan A, Judd AS, Mulhem M, Brodjian S, Dayton B, Shapiro R et al: Identification of 2-<4- benzyloxyphenyl)-N-[1-<2-pyiTolidin-1-yl-ethvl)-1H-indazol-6-yl]acetamide, an orally efficacious melanin-concentrating hormone receptor 1 antagonist for the treatment of obesity. J Med Chem (2005) 48(5):1318-1321.
55. Souers AJ, Gao J, Wodka D, Judd AS, Mulhern MM, Napier JJ, Brune ME, Bush EN, Brodjian SJ, Dayton BD, Shapiro R et at. Synthesis and evaluation of urea-based indazoles as melanin-concentrating hormone receptor 1 antagonists for the treatment of obesity. Bioorg Med Chem Lett (2005) 15(11):2752-2757.
56. Vasudevan A, Verzal MK, Wodka D, Souers AJ, Blackburn C, Che JL, Lai S, Brodjian S, Falls DH, Dayton BD, Govek E et al: Identification of aminopiperidlne benzamides as MCHR1 antagonists. Bioorg Med Chem Lett (2005) 15(14):3412-3416.
57. Vasudevan A, LaMarche MJ, Blackburn C, Che JL, Luchaco-Cullis CA, Lai S, Marsilje TH, Patane MA, Souers AJ, Wodka D, Geddes B et al: Identification of ortho-amino benzamides and nicotinamides as MCHR1 antagonists. Bioorg Med Chem Lett (2005) 15(19):4174-4179.
58. Vasudevan A, Souers AJ, Freeman JC, Verzal MK, Gao J, Mulhem MM, Wodka D, Lynch JK, Engstrom KM, Wagaw SH, Brodjian S et al: Aminopiperidine indazoles as orally efficacious melanin concentrating hormone receptor-1 antagonists. Bioorg Med Chem Lett (2005) 15(23):5293-5297.
59. Kanuma K, Omodera K, Nishiguchi M, Funakoshi T, Chaki S, Semple G, Tran TA, Kramer B, Hsu D, Casper M, Thomsen B et al: Discovery of 4-(dimethylamlno)quinazolines as potent and selective antagonists for the melanin-concentrating hormone receptor 1. Bioorg Med Chem Lett (2005) 15(10):2565-2569.
60. Kanuma K, Omodera K, Nishiguchi M, Funakoshi T, Chaki S, Nagase Y, Iida I, Yamagucni JI, Semple G, Tran T-A, Sekiguchi Y: Identification of 4-amino-2-cyclohexylaminoquinazolines as metabolically stable melanin-concentrating hormone receptor 1 antagonists. Bioorg Med Chem (2006): in press.
61. Chaki S, Funakoshi T, Hirota-Okuno S, Nishiguchi M, Shimazaki T, Iijima M, Grottick AJ, Kanuma K, Omodera K, Sekiguchi Y, Okuyama S et al: Anxiolytic- and antidepressant-like profile of ATC0065 and ATC0175: Nonpeptldic and orally active melanin-concentrating hormone receptor 1 antagonists. J Pharmacol Exp Ther (2005) 313(2):831-839. Documents the anxiolytic and antidepressant effects of an orally active MCH-1R antagonist.
62. Kanuma K, Omodera K, Nishiguchi M, Funakoshi T, Chaki S, Semple G, Tran TA, Kramer B, Hsu D, Casper M, Thomsen B et al. Lead optimization of 4-(dimethylamino)quinazolines, potent and selective antagonists for the melanin-concentrating hormone receptor 1. Bioorg Med Chem Lett (2005) 15(17):3853-3856.
63. IDdb Drug Report: Human MCH receptor 1 antagonists (obesity), Arena/Taisho. Thomson Scientific, London, UK (2006). http://www.iddb.com/iddb3/ iddb3_2/reports.display?id=51000&template= Drug&i_query_id=6917212
64. Chaki S, Yamaguchi J, Yamada H, Kanuma K, Sekiguchi Y: Melanin-concentrating hormone receptor 1 antagonists for the treatment of depression and anxiety. Drug Dev Res (2005) 65(4):278-290. Describes extensive studies on the anxiolytic and antidepressive effects of treatment with an MCH-1R antagonist.
65. Dyck B: Small molecule melanin-concentrating hormone receptor 1 (MCH1R) antagonists as anxiolytic and antidepressive agents. Drug Dev Res (2005) 65(4):291-300. Describes extensive studies on the anxiolytic and antidepressive effects of treatment with an MCH-1R antagonist.
66. Huang CQ, Baker T, Schwarz D, Fan J, Heise CE, Zhang M, Goodfellow VS, Markison S, Gogas KR, Chen T, Wang XC et al: 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 (2005) 15(16):3701-3706.
67. 1 antagonist in conjunction with an MCH-1R antagonist for the treatment of obesity.
68. Bohlooly-Y M, Mahlapuu M, Andersen H, Astrand A, Hjorth S, Svensson L, Tomell J, Snaith MR, Morgan DG, Ohlsson C: Osteoporosis in MCHR1 -deficient mice. Biochem Biophys Res Comm (2004) 318(4):964-969.
69. Adamantidis A, Thomas E, Foidart A, Thyon A, Coumans B, Minet A, Tirelli E, Seutin V, Grisar T, Lakaye B: Disrupting the melanin-concentrating hormone receptor 1 in mice leads to cognitive deficits and alterations of NMDA receptor function. Eur J Neuroscience (2005) 21(10):2837-2844.