Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases


Hypothalamic receptors for neuropeptide Y, melaninconcentrating hormone, melanocortins and orexins/ hypocretins as well as for the downstream signaling corticotrophic factor have been discussed broadly for their influence on food intake and reward but also on several psychiatric disorders. For the development of non-peptide ligands for the in vivo detection of alterations in density and affinity of such G-protein coupled (GPCRs) peptide receptors the requirements to affinity and pharmacokinetics have been shifted to thresholds markedly distict from classical GPCRs to dissociation constants < 0.5 nM, partition coefficients log P < 3.5 and transcellular transport ratios, e.g. for the permeability glycoprotein transporter, below 3. Nevertheless, a multitude of compounds has been reported originally as potential therapeutics in the treatment of obesity among which some are suitable candidates for labeling as PET or SPECT-tracers providing receptor affinities even below 0.1 nM. These could be unique tools not only for better understanding of the mechanism of obesity but also for investigations of extrahypothalamic role of “feeding receptors” at the interface between neuroendocrine and mental diseases.

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Pissarek, M. and Disko, U. (2013) Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases. World Journal of Neuroscience, 3, 100-125. doi: 10.4236/wjns.2013.32014.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Owen, M.J. and Nemeroff, C.B. (1999) Corticotropin-releasing factor antagonists in affective disorders. Expert Opinion on Investigational Drugs, 8, 1849-1858. doi:10.1517/13543784.8.11.1849
[2] Hokfelt, T., Broberger, C., Xu, Z.-Q.D., Sergeyev, V., Ubink, R. and Diez, M. (2000) Neuropeptides—An overview. Neuropharmacology, 39, 1337-1356. doi:10.1016/S0028-3908(00)00010-1
[3] Marchetti, B., Morale, M.C., Gallo, F., Lomeo, E., Testa, N., Tirolo, C. and Caniglia Garozzo, G. (2001) Thhypothalamo-pituitary-gonadal axis and the immunesystem. In: Ader, R., Felten, D.L. and Cohen, N., Eds., Psychoneuroimmunology, 3rd Edition,Academic Press, San Diego, 363-389.
[4] Chaki, S. and Kanuma, K. (2007) Neuropeptide receptors: Novel therapeutic targets for depression and anxiety disorders. Drugs of the Future, 32, 809-822. doi:10.1358/dof.2007.032.09.1131450
[5] Nemeroff, C.B. (2008) Recent findings in the pathophysiology of depression. Focus, 6, 3-14.
[6] Schottelius, M. and Wester, H.-J. (2009) Molecular imaging targeting peptide receptors. Methods, 48, 161-177. doi:10.1016/j.ymeth.2009.03.012
[7] Appleyard, S., Hayward, M., Young, J.I., Butler, A.A., Cone, R.D., Rubinstein, M. and Low, M.J. (2003) A role for the endogenous opioid β-endorphin in energy homeostasis. Endocrinology, 14, 1753-1760. doi:10.1210/en.2002-221096
[8] Dunn, A.J., Swiergiel, A.H. and Palamarchouk, V. (2004) Brain circuits involved in corticotrophin releasing factor-norepinephrine interactions during stress. Annals of the New York Academy of Sciences, 1018, 25-34. doi:10.1196/annals.1296.003
[9] Coll, A.P. (2007) Effects of pro-opiomelanocortin (POMC) on food intake and body weight: Mechanisms and therapeutic potential? Clinical Science, 113, 171-182. doi:10.1042/CS20070105
[10] Holmes, A., Heilig, M., Rupniak, N.M.J., Steckler, T. and Griebel, G. (2003) Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders. Trends in Pharmacological Sciences, 24, 580-588. doi:10.1016/
[11] Inui, A. (2003) Neuropeptide gene polymorphism and human behavioural disorders. Nature Reviews Drug Discovery, 2, 986-998. doi:10.1038/nrd1252
[12] Moosa, M.Y.H. and Jeenah, F.Y. (2008) Orexin—Does it have a role in mental illness? South African Journal of Psychiatry, 14, 63-64.
[13] Stahl, S.M. and Wise, D.D. (2008) The potential role of a corticotrophin-releasing factor receptor-1 antagonist in psychiatric disorders. CNS Spectrums, 13, 467-472, 476-483.
[14] Giesbrecht, C.J., Mackay, J.P., Silveira, H.B., Urban, J.H. and Colmers, W.F. (2010) Countervailing modulation of Ih by neuropeptide Y and corticotrophin-releasing factor in basolateral amygdale as a possible mechanism for their effects on stress-related behavior. The Journal of Neuroscience, 30, 1670-16982. doi:10.1523/JNEUROSCI.2306-10.2010
[15] Zorilla, E.P. and Koob, G.F. (2010) Progress in corticotrophin-releasing factor-1 antagonist development. Drug Discovery Today, 15, 371-383. doi:10.1016/j.drudis.2010.02.011
[16] Refojo, D., Schweizer, M., Kuehne, C., Ehrenberg, S., Thoeringer, C., Schumacher, M., von Wolff, G., Avrabos, C., Touma, C., Engbliom, D., Schütz, E., Nave, K.-A., Eder, M., Wotjak, C.T., Sillaber, I., Holsboer, F., Wurst, W. and Deussing, J.M. (2011) Glutamatergic and dopaminergic neurons mediate anxiogenic and anxiolytic effects of CRHR1. Science, 333, 1903-1907.
[17] Fahmy, H., Spyridaki, K., Kuppast, B. and Liapakis, G. (2012) The homeostasis hormone and its CRF1 receptor. From structure to function. Hormones, 11, 254-271.
[18] Schwartz, M.W., Woods, S.C., Porte Jr., D., Seeley, R.J. and Baskin, D.G. (2000) Central nervous system control of food intake. Nature, 404, 661-671.
[19] Stanley, S., Wynne, K., McGowan, B. and Bloom, S. (2005) Hormonal regulation of food intake. Physiological Reviews, 85, 1131-1158. doi:10.1152/physrev.00015.2004
[20] Wikberg, J.E.S. and Mutulis, F. (2008) Targeting melanocortin receptors: An approach to treat weight disorders and sexual dysfunction. Nature Reviews Drug Discovery, 7, 307-323. doi:10.1038/nrd2331
[21] Büch, T.R.H., Heling, D., Damm, E., Gudermann, T. and Reit, A. (2009) Pertussis toxin-sensitive signaling of melanocortin-4 receptor in hypothalamic GT1-7 cells defines Agouti-related protein as a biased agonist. The Journal of Biological Chemistry, 284, 26411-26420. doi:10.1074/jbc.M109.039339
[22] Bethge, N., Diel, F., Rosick, M., and Holz, J. (1981) Somatostatin half-life: A case report in one health volunter and a three month follow up. Hormone and Metabolic Research, 13, 709-710. doi:10.1055/s-2007-1019383
[23] Ehrstrom, M., Naslund, E., Levin, F., Kaur, R., Kitchgessner, A.L., Theodorsson, E. and Hellstrom, P.M. (2004) Pharmacokinetic profile of orexin A and effects on plasma insulin and glucagon in the rat. Regulatory Peptides, 119, 209-212. doi:10.1016/j.regpep.2004.02.004
[24] Kastin, A.J., Pan, W., Maness, L.M. and Banks, W.A. (1999) Peptides crossing the blood-brain barrier: Some unusal observations. Brain Research, 848, 96-100. doi:10.1016/S0006-8993(99)01961-7
[25] Kastin, A., Akerstrom, V. and Hackler, L. (2000) Agouti-related protein (83-132) aggregates and crosses the blood-brain barrier slowly. Metabolism, 49, 1444-1448. doi:10.1053/meta.2000.16556
[26] Banks, W.A. (2006) Blood brain barrier and energy balance. Obesity, 14, 234S-237S. doi:10.1038/oby.2006.315
[27] Banks, W.A. (2008) Delivery of peptides to the brain: Emphasis on therapeutic development. Peptide Science, 90, 589-593.
[28] Zilow, G., Zilow, E.P., Burger, R. and Lindenkamp, O. (1993) Complement activation in newborn infants with early onset infection. Pediatric Research, 34, 199-203. doi:10.1203/00006450-199308000-00020
[29] Akopjan, T.N., Arutiunian, A.A., Laita, A. and Galoian, A.A. (1978) Breakdown of luliberin, somatostatin and substance P as an effect of hypothalamic endopeptidases. Voprosy Biokhimii Mozga, 13, 189-205.
[30] Grouzmann, E., Fathi, M., Gillet, M., de Torrentè, A., Cavadas, C., Brunner H. and Buclin, T. (2001) Disappearance rate of catecholamines, total metanephrines, and neuropeptide Y from the plasma of patients after resection of pheochromocytoma. Clinical Chemistry, 47, 1075-1082.
[31] Foley, K.M., Kourides, I.A., Inturrisi, C.E., Kaiko, R.F., Zaroulis, C.G., Posner, J.B., Houde, R.W. and Li, C.H. (1979) β-Endorphin: Analgesic and hormonal effects in humans. Proceedings of the National Academy of Sciences of the United States of America, 76, 5377-5381. doi:10.1073/pnas.76.10.5377
[32] Lipinski, C.A. (2000) Drug-like properties and the causes of poor solubility and poor permeability. Journal of Pharmacological and Toxicological Methods, 44, 235-249. doi:10.1016/S1056-8719(00)00107-6
[33] Reubi, J.C. (1995) Neuropeptide receptors in health and disease: the molecular basis for in vivo imaging. Journal of Nuclear Medicine, 36, 1825-1835.
[34] Egleton R.D. and Davis, T.P. (2005) Development of neuropeptide drugs that cross the blood-brain barrier. NeuroRx Research, 2, 44-53. doi:10.1602/neurorx.2.1.44
[35] Reubi, J.C. (2003) Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocrine Reviews, 24, 389-427. doi:10.1210/er.2002-0007
[36] Patel, D. and Patel, M (2010) Review of NPY and NPY receptor for obesity. Internet Journal of Pharmacology, 8, 8. doi:10.5580/2531
[37] Bednarek, M.A. and Fong, T.M. (2004) Ligands of the melanocortin receptors, 2002-2003. Expert Opinion on Therapeutic Patents, 14, 327-336. doi:10.1517/13543776.14.3.327
[38] Lerner, E.N., van Zanten, E.H. and Stewart, G.R. (2004) Enhanced delivery of octreotide to the brain via transnasal iontophoretic administration. Journal of Drug Targeting, 12, 273-280. doi:10.1080/10611860400000938
[39] Blankeney, J.S., Reid, R.C., Le, G.T. and Fairlie, O.P. (2007) Nonpeptidic ligands for peptide-activated G protein-coupled receptors. Chemical Reviews, 107, 2960-3041. doi:10.1021/cr050984g
[40] Betancur, C., Azzi, M. and Rostene, W. (1997) Nonpeptide antagonists of neuropeptide receptors: Tools for research and therapy. Treasury Inflation Protected Securities, 18, 372-386. doi:10.1016/S0165-6147(97)90666-0
[41] Klabunde, T. and Hessler, G. (2002) Drug design strategies for targeting G-Protein-coupled receptors. ChemBio-Chem, 3, 928-944. doi:10.1002/1439-7633(20021004)3:10<928::AID-CBIC928>3.0.CO;2-5
[42] Chen, Y.L., Mansbach, R.S., Winter, S.M., Brooks, E., Collins, J., Corman, M.L., Dunaiskis, A.R., Faraci, W.S., Gallaschun, R.J., Schmidt, A. and Schulz, D.W. (1997) Synthesis and oral efficacy of a 4-butylethylamino)pyrrolo [2,3-d]pyrimidine: A centrally active corticotrophin-releasing factor 1receptor antagonist. Journal of Medicinal Chemistry, 40, 1749-1754. doi:10.1021/jm960861b
[43] Zobel, A.W., Nickel, T., Kunzel, H.E., Ackl, N., Sonntag, A., Ising, M. and Holsboer, F. (2000) Effect of high affinity corticotrophin-releasing hormone receptor 1 antagonist R121919 in major depression: The first 20 patients treated. Journal of Psychiatric Research, 34, 171-181. doi:10.1016/S0022-3956(00)00016-9
[44] Gully, D., Geslin, M., Serva, L., Fontaine, E., Roger, P., Lair, C., Darre, V., Marcy, C., Rouby, P.-E., Simiand, J., Guitard, J., Gout, G., Steinberg, R., Rodier, D., Griebel, G., Soubrie, P., Pascal, M., Pruss, R., Scatton, B., Maffrand, G.-P. and Le Fur, G. (2002) 4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A): A potent and selective corticotrophin-releasing factor1 receptor antagonist. I. Biochemical and pharmacological characterization. Journal of Pharmacology and Experimental Therapeutics, 301, 322-332. doi:10.1124/jpet.301.1.322
[45] Gutman, D.A, Owens, M.J., Skelton, K.H., Thrivikraman, K.V. and Nemeroff, C.B. (2003) The corticotropin-releasing factor1 receptor antagonist R121919 attenuates the behavioral and endocrine responses to stress. Journal of Pharmacology and Experimental Therapeutics, 304, 874-880. doi:10.1124/jpet.102.042788
[46] Barbosa, H.J., Collins, E.A., Hamdouchi, C., Hembre, E.J., Hipskin, P.A., Johnston, R.D., Lu, J., Rupp, M.J., Takakuwa, T. and Johnston, R.C. (2006) Imidazopyridazine compounds. WO2006102194.
[47] Yoon, T., de Lombaert, S., Brodbeck, R., Gulianello, M., Krause, J.E., Hutchinson, A., Horvath, R.F., Ge, P., Kehne, J., Hoffman, D., Chandrasekhar, J., Doller, D. and Hodgetts, K.-J. (2008) 2-Arylpyrimidines: Novel CRF-1 receptor antagonists. Bioorganic & Medicinal Chemistry Letters, 18, 4438-4490. doi:10.1016/j.bmcl.2008.07.063
[48] Boss, C., Brisbare-Roch, C., Jenck, F., Aissaoui, H., Koberstein, R., Sifferlen, T. and Weller, T. (2008) Orexin receptor antagonism: A new principle in neuroscience. CHIMIA International Journal for Chemistry, 62, 974-979. doi:10.2533/chimia.2008.974
[49] Cox, C.D., Breslin, M.J., Whitman, D.B., Schreier, J.D., McGaughey, G.B., Bogusky, M.J., Roecker, A.J., Mercer, S.P., Bednar, R.A., Lemaire, W., Bruno, J.G., Reiss, D.R, Harrell, C.M, Murphy, K.L., Garson, S.L., Doran, S.M., Prueksaritanont, T., Anderson, W.B., Tang, C., Roller, S., Cabalu, T.D., Cui, D., Hartman, G.D., Young, S.D., Koblan, K.S., Winrow, C.J., Renger, J.J. and Coleman, P.J. (2010) Discovery of the dual receptor antagonist [(7R)-4-(5-Chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia. Journal of Medicinal Chemistry, 53, 5320-5332. doi:10.1021/jm100541c
[50] Dvorak, C.A., Swanson, D.M., Wong, V.D. (2009) Piperazinyl derivatives useful as modulators of the neuropeptide Y2 receptor. WO2009/006185, US2008/068289, 2010.
[51] Shoblock, J.R., Welty, N., Nepomuceno, D., Lord, B., Aluisio, L., Fraser, I., Motley, S.T., Sutton, S.W., Morton, K., Galici, R., Attack, J.R., Dvorak, L., Swanson, D.M., Carruthers, N.I., Dvorak, C., Lovenberg, T.W. and Bonaventure, P. (2010) In vitro and in vivo characterization of JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phe-nylethyl]piperazin-1yl}-flurophenyl)-2pyridin-3-ylbenzamide), a selective brain penetrant small molecule antagonist of the neuropeptide YY2 receptor. Psychopharmacology, 208, 265-277. doi:10.1007/s00213-009-1726-x
[52] Burke, T.R., Rice, K.C. and Pert, C.B. (1985) Probes for narcotic receptor mediated phemomena. II. Synthesis of 17-methyl and 17-cyclopropylmethyl-3,14-dihydroxy-4,5-alpha-epoxy-6-beta-fluoromorphinans (foxy and cyclofoxy) as models of opioid ligands suitable for positron emission transaxial tomography. Heterocycles, 23, 69-99.
[53] Kask, A., Rago, L., Korrovits, P., Wikberg, J.E.S. and Schioth, H.B. (1998) Evidence that orexigenic effects of melanocortin C receptor antagonist HS014 are mediated by neuropeptide Y. Biochemical and Biophysical Research Communications, 248, 245-249. doi:10.1006/bbrc.1998.8961
[54] Chaki, S., Hirota, S., Funakoshi, T., Suzuki, Y., Suetake, S., Okubo, T., Ishii, T., Nakazato, A. and Okuyama, S. (2003) Anxiolytic-like and antidepressant-like activities of MCL0129 (1-[(S)-2-(4-fluorophenyl)-2-(4-iso-propylpiperadin-1-yl-)ethyl]-4-[4-(2-met hoxynaphthalen-1-yl)butyl] piperazine), a novel and potentnonpeptide antagonist of the melanocortin-4 receptor. Journal of Pharmacology and Experimental Therapeutics, 304, 818-826. doi:10.1124/jpet.102.044826
[55] Takekawa, S., Asami, A., Ishihara, Y., Terauchi, J., Kato, K., Shimomura, Y., Mori, M., Murakoshi, H., Suzuki, N., Nishimura, O. and Fujino, M. (2002) T226296: A novel, orally active and selective melanin-concentrating hormone receptor antagonist. European Journal of Pharmacology, 438, 129-135. doi:10.1016/S0014-2999(02)01314-6
[56] Kato, H., Kuwako, K.I., Suzuki, M. and Tanaka, S. (2004) Gene expression patterns of pro-opiomelanocortin-processing enzymes PC1 and PC2 during postnatal development of rat corticotrophs. Journal of Histochemistry & Cytochemistry, 52, 943-957. doi:10.1369/jhc.4A6276.2004
[57] Tokunaga, T., Hume, W.E., Nagamine, J., Kawamura, T., Taiji, M. and Nagata, R. (2005) Structure-activity relationships of the oxindole growth hormone secretagogues. Bioorg. Bioorganic & Medicinal Chemistry Letters, 15, 1789-1792. doi:10.1016/j.bmcl.2005.02.042
[58] Tomita, D., Yamatsugu, K., Kanai, M. and Shibasaki, M., (2009) Enantioselctive synthesis of SM-130686 based on the development of asymmetric Cu (I9F catalysis to access 2-oxindoles containing a tetrasubstituted carbon. Journal of the American Chemical Society, 131, 6946-6948. doi:10.1021/ja901995a
[59] Vale, W., Spiess, J. and Rivier, C. (1981) Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science, 213, 1394-1397. doi:10.1126/science.6267699
[60] Huising, M.O., Vaughan, J.M., Shah, S.H., Grillot, K.L., Donaldson, C., Rivier, J., Flik, G. and Vale, W.W. (2008) Residues of corticotrophin releasing factor-binding protein (CRF-BP) that selectively abrogate binding to CRF but not to urocortin. The Journal of Biological Chemistry, 283, 8902-8912. doi:10.1074/jbc.M709904200
[61] Sawchenko, P.E. and. Swanson, L.W. (1981) A method for tracing biochemically defined pathways in the central nervous system using combined fluorescence retrograde transport and immunohistochemical techniques. Brain Research, 210, 31-51. doi:10.1016/0006-8993(81)90882-9
[62] Sullivan, G.M., Parsey, R.V., Kumar, J.S.D., Arango, V., Kassir, S.A., Huang, Y.-Y., Simpson, N.R., van Heertum, R.L. and Mann, J.J. (2007) PET imaging of CRF1 with [11C] R121919 and [11C]DMP696, is the target of sufficient density. Nuclear Medicine and Biology, 34, 353-361. doi:10.1016/j.nucmedbio.2007.01.012
[63] De Souza, E.B. (1995) Corticotropin releasing factor receptors: Physiology, pharmacology, biochemistry and role in central nervous system and immune disorders. Psychoneuroendocrinology, 20, 789-819. doi:10.1016/0306-4530(95)00011-9
[64] Kolakowski, L.F. (1994) GCRDb: A G-protein-coupled receptor database. Receptors & Channels, 2, 1-7.
[65] Horn, F., Vriend, G. and Cohen, F.E. (2001) Collecting and harvesting biological data: The GPCRDB and NuclearDB information systems. Nucleic Acids Research, 29, 346-349. doi:10.1093/nar/29.1.346
[66] Davies, M.N., Secker, A., Freitas, A.A., Mendao, M., Timmis, J. and Flowe, D.R. (2007) On the hierarchical classification of G protein coupled receptors. Bioinformatics, 23, 3113-3118. doi:10.1093/bioinformatics/btm506
[67] Parthier, C., Reedtz-Runge, S., Rudolph, R. and Stubbs, M.T. (2009) Passing the baton in class B GPCRs: Peptide hormone activation via helix induction? Trends in Biochemical Sciences, 34, 303-310. doi:10.1016/j.tibs.2009.02.004
[68] Suwa, M., Sugihara, M. and Ono, Y. (2011) Functional and structural overview of G-protein-coupled receptors comprehensively obtained from genom sequences. Pharmaceuticals, 4, 652-664. doi:10.3390/ph4040652
[69] Unla, H. and Karnik, S.S. (2012) Domain coupling in GPCRs: The engine for induced conformational changes. Treasury Inflation Protected Securities, 33, 79-88. doi:10.1016/
[70] Dautzenberg, F.M., Kilpatrick, G.J., Hauger, R.L. and Moreau, J. (2001) Molecular biology of the CRH recaptors—In the mood. Peptides, 22, 753-760. doi:10.1016/S0196-9781(01)00388-6
[71] Gutknecht, E., van der Linden, I., van Kolen, K., Verhoeven, K.F.C., Vauqelin, G. and Dautzenberg, F.M. (2009) Molecular mechanisms of corticotrophin-releasing factor receptor-induced calcium signalling. Molecular Pharmacology, 75, 648-657. doi:10.1124/mol.108.050427
[72] Millan, M.A., Samra, A.B., Wynn, P.C., Catt, K.J. and Aguilera, G. (1987) Receptors and actions of corticotrophin-releasing hormone in the primate pituitary gland. The Journal of Clinical Endocrinology & Metabolism, 64, 1036-1041. doi:10.1210/jcem-64-5-1036
[73] Hauger, R.L., Lorang, M., Irwin, M. and Aguilera, G. (1990) CRF receptor regulation and sensitization of ACTH response to acute ether stress during chronic intermittent immobilization stress. Brain Research, 532, 34-40. doi:10.1016/0006-8993(90)91738-3
[74] Millan, M.A., Jacobowitz, D.M., Hauger, R.L., Catt, K.J. and Aguilera, G. (1986) Distribution of corticotrophin-releasing factor receptors in primate brain. Proceedings of the National Academy of Sciences of the United States of America, 83, 1921-1925. doi:10.1073/pnas.83.6.1921
[75] Madaan, V. and Wilson, D. (2009) Neuropeptides: Relevance in treatment of depression and anxiety disorders. Drug News & Perspectives, 22, 319-324. doi:10.1358/dnp.2009.22.6.1395255
[76] Werner, F.-M. and Covenas, R. (2010) Classical neurotransmitters and neuropeptides involved in major depression: A review. International Journal of Neuroscience, 120, 455-470. doi:10.3109/00207454.2010.483651
[77] Hoare, S.R.J., Sullivan, S.K., Fan, J., Khongsaly, K. and Grigoriadis, D.E. (2005) Peptide ligand binding properties of the corticotrophin-releasing factor (CRF) type 2 receptor: Pharmacology of endogenously expressed receptors, G-protein-coupling sensitivity and determinants of CRF2 receptor selectivity. Peptides, 26, 457-470. doi:10.1016/j.peptides.2004.10.019
[78] Lovenberg, T.W., Liaw, C.W., Grigoriadis, D.M., Clevenger, W., Chalmers, D., De Souza, E.B. and Oltersdorf, T. (1995) Cloning and characterization of a functionally distinct corticotropin-releasing factor receptor subtype from rat brain. Proceedings of the National Academy of Sciences of the United States of America, 92, 836-840. doi:10.1073/pnas.92.3.836
[79] Chalmers, D.T., Lovenberg, T.W. and DeSouza, E.B. (1995) Localization of novel corticotrophin-releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: Comparison with CRF1 receptor mRNA expression. The Journal of Neuroscience, 15, 6340-6350.
[80] Kostich, W.A., Chen, A., Sperle, K. and Largent, B.L. (1998) Molecular identification and analysis of a novel human corticotropin-releasing factor (CRF) receptor: The CRF2 receptor. Molecular Endocrinology, 12, 1077-1085. doi:10.1210/me.12.8.1077
[81] Baigent, S.M. and Lowry, P.J. (2000) mRNA expression profiles for corticotrophin-releasing factor (CRF), urocortin, CRF-receptors and CRF-binding protein in peripheral rat tissues. Journal of Molecular Endocrinology, 25, 43-52. doi:10.1677/jme.0.0250043
[82] Vaughan, J., Donaldson, C., Bittencourt, J., Perrin, M.H., Lewis, K., Sutton, S., Chan, R., Turnbull, A.V., Lovejoy, D., Rivier, C., Rivier, J., Sawchenko, P.E. and Vale, W. (1995) Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature, 378, 287-292. doi:10.1038/378287a0
[83] Rühmann, A., Chapman, J., Higelin, J., Butscha, B. and Dautzenberg, F.M. (2002) Design, synthesis and pharmacological characterization of new highly selective CRF2 antagonist: Development of 123I-K31440 as a potential SPECT ligand. Peptides, 23, 453-460. doi:10.1016/S0196-9781(01)00640-4
[84] Kehne, J.H. and Cain, C.K. (2010) Therapeutic utility of non-peptidic CRF1 receptor antagonists in anxiety, depression and stress-related disorders: evidence from animal models. Pharmacology & Therapeutics, 128, 460-487. doi:10.1016/j.pharmthera.2010.08.011
[85] Schulz, D.W. Mansbach, R.S., Sprouse, J., Braselton, J.P., Collins, J., Corman, M., Dunaiskis, A., Faraci, S., Schmit, A., Chen, Y. and Heym, J. (1996) CP-154,526: A potent and selective nonpeptide antagonist of corticotrophin releasinf factor receptors. Proceedings of the National Academy of Sciences of the United States of America, 93, 10477-10482. doi:10.1073/pnas.93.19.10477
[86] Whitten, J.P., Xie, X.F., Erickson, P.E., Webb, T.R., De-Souza, E.B., Grigoriadis, D.E. and McCarthy, J.R. Rapid microscale synthesis, a new method for lead optimization using robotics and solution phase chemistry: Application to the synthesis and optimization of corticotropin releasing factor 1 receptor antagonists. Journal of Medicinal Chemistry, 39, 4354-4357. doi:10.1021/jm960148m
[87] Gehlert, D.R., Cippitelli, A., Thorsell, A., D. Le, A.D., Hipskind, P.A., Hamdouchi, C., Lu, J., Hembre, E.J., Cramer, J., McKinzie, D., Morin, M., Ciccocioppo, R. and Heilig, M. (2007) 3-(4-Chloro-2-morpholin-4-ylthiazol-5-yl)-8-(1-ethylpropyl-2,6-dimethyl-imidazo[1,2-b] pyridazine: A novel brain penetrant, orally available corticotropin releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism. The Journal of Neuroscience, 27, 2718-2726. doi:10.1523/JNEUROSCI.4985-06.2007
[88] Chen, C., Wilcoxen, K.M., Huang, C.Q., Xie, Y.-F., McCarthy, J.R., Webb, T.R., Zhu, Y.-F., Saunders, J., Liu, X.-J., Chen, T.K., Bozigian, H. and Grigoriadis, D.E. (2004) Design of 2,5-Dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino-pyrazolo[1,5-a]pyrimidine (NBI 30775/R121919) and structure activity relationships of a series of potent and orally active corticotrophin-releasing factor receptor antagonists. Journal of Medicinal Chemistry, 47, 4787-4798. doi:10.1021/jm040058e
[89] Seymour, P.A., Schmidt, A. W. and Schulz, D.W. (2003) The pharmacology of CP-154, 526, a non-peptide antagonist of the CRH1 receptor: A review. CNS Drug Reviews, 9, 57-96. doi:10.1111/j.1527-3458.2003.tb00244.x
[90] Hodgetts, K.J., Ge, P., Yoon, T., de Lombaert, S., Brodbeck, R., Gulianello, M., Kieltyka, A., Horvath, R.F., Kehne, J.H., Krause, J.E., Maynard, G.D., Hoffmann, D., Lee, Y., Fung, L. and Doller, D. (2011) Discovery of N-(1-ethylpropyl)-3-methoxy-5-(2-methoxy-4-trifluoromethoxyphenyl) 6-methyl-pyrazin-2yl]amine 59 (NGD 98-2): An orally active corticotrophin releasing factor-1 (CRF-1) receptor antagonist. Journal of Medicinal Chemistry, 54, 4187-4206. doi:10.1021/jm200365y
[91] Martarello, L., Kilts, C.D., Ely, T., Owens, M.J., Nemeroff, C.B., Camp, M. and Goodman, M.M. (2001) Synthesis and characterization of fluorinated and iodinated pyrrolopyrimidines as PET/SPECT ligands for the CRF1 receptor. Nuclear Medicine and Biology, 28, 187-195. doi:10.1016/S0969-8051(00)00199-2
[92] Hsin, L.W., Webster, E.L., Chrousos, G.P., Gold, P.W., Eckelman, W.C., Contoreggi, C. and Rice, K.G. (2000) Synthesis and biological activity of fluoro-substituted pyrrolo[2,3-d] pyrimidines: The development of potential positron emission tomography imaging agents for the corticotrophin-releasing hormone type 1receptor. Bioorganic & Medicinal Chemistry Letters, 10, 707-710. doi:10.1016/S0960-894X(00)00071-8
[93] Zuev, D., Mattson, R.J., Huang, H., Mattson, G.K., Zueva, L., Nielsen, M., Kozlowski, E.S., Huang, X.S., Dedong, W., Gao, Q., Lodge, N.J., Bronson, J.J. and Macor, J.E. (2011) Potential CRF1 R PET imaging agents: N-Fluoroalkyl-8-(6-methoxy-2-methyl-pyridin-3-yl)-2,7-dimethyl-N-alkylpyrazolo[1,5-a][1,3,5]triazin-4-amines. Bioorganic & Medicinal Chemistry Letters, 21, 2484-2488. doi:10.1016/j.bmcl.2011.02.050
[94] Richardson, H.N., Zhao, Y., Fekete, E.M., Funk, C.K., Wirsching, P., Janda, K.D., Zorilla, E.P. and Koob, G.F. (2008) MPZP: A novel small molecule corticotrophin-releasing factor type 1 receptor (CRF1) antagonist. Pharmacology Biochemistry and Behavior, 88, 497-510. doi:10.1016/j.pbb.2007.10.008
[95] Jagoda, E.M., Lang, L., McCullough, K., Contoreggi, C., Moon, K.B., Ma, Y., Rice, K.C., Szajek, L.P., Eckelman, W.C. and Kiesewetter, D.O. (2011) [76Br] BMK-152, a nonpeptide analogue, with high affinity and low nonspecific binding for the corticotrophin-releasing factor type 1 receptor. Synapse, 65, 910-918. doi:10.1002/syn.20919
[96] Tatemoto, K., Carlquist, M. and Mutt, V. (1982) Neuropeptide Y—A novel brain peptide with structural similarities to peptide YY and pancreatic polypeptide. Nature, 296, 659-660. doi:10.1038/296659a0
[97] Herzog, H., Hort, Y.J., Ball, H.J., Hayes, G., Shine, J. and Selbie, L.A. (1992) Cloned human neuropeptide Y receptor couples to two different second messenger systems. Proceedings of the National Academy of Sciences of the United States of America, 89, 5794-5798. doi:10.1073/pnas.89.13.5794
[98] Larhammar, D., Blomqvist, A.G., Yee, F., Jazin, E., Yoo, H. and Wahlestedt, C. (1992) Cloning and functional expression of a human neuropeptide Y/peptide YY receptor of the Y1 type. The Journal of Biological Chemistry, 267, 10935-10938.
[99] Parill, A.L. and Bautista, D.L. (2011) GPCR conformations: Implications for rational drug design. Pharmaceuticals, 4, 7-43. doi:10.3390/ph4010007
[100] Inui, A. (2003) Neuropeptide gene polymorphism and human behavioural disorders. Nature Reviews Drug Discovery, 2, 986-998. doi:10.1038/nrd1252
[101] Kamiji, M.M. and Inui, A. (2007) Neuropeptide Y recaptor selective ligands in the treatment of obesity. Endocrine Reviews, 28, 664-684. doi:10.1210/er.2007-0003
[102] Wisialowski, T., Parker, R., Preston, E., Sainsbury, A., Kraegen, E., Herzog, H. and Cooney, G. ( 2000) Adrenalectomy reduces neuropeptride Y-induced insulin release and NPY receptor expression in the rat ventromedial hypothalamus. The Journal of Clinical Investigation, 105, 1253-1259. doi:10.1172/JCI8695
[103] Sato, N., Ogino, Y., Mashiko, S. and Ando, M. (2009) Modulation of neuropeptide Y receptors for the treatment of obesity. Expert Opinion on Therapeutic Patents, 19, 1401-1415. doi:10.1517/13543770903251722
[104] Chee, M.J.S., Myers, M.G., Price, C.J. and Colmers, W.F. (2010) Neuropeptide Y suppresses anorexic output from the ventromedial nucleus of the hypothalamus. The Journal of Neuroscience, 30, 3380-3390. doi:10.1523/JNEUROSCI.4031-09.2010
[105] Marston, O.J., Hurst, P., Evans, M.L., Burdakov, D.I. and Heisler, L.K. (2011) Neuropeptide Y cells represent a distinct glucose-sensing population in the lateral hypothalamus. Endocrinology, 152, 4046-4052. doi:10.1210/en.2011-1307
[106] Yulyaningsih, E., Zhang, L., Herzog, H. and Sainsbury, A. (2011) NPY receptors as potential targets for anti-obesity drug development. British Journal of Pharmacology, 163, 1170-1202. doi:10.1111/j.1476-5381.2011.01363.x
[107] Bowers, M.E., Choi, D.C. and Ressler, K.J. (2012) Neuropeptide regulation of fear and anxiety: Implications of cholecystokinin, endogenous opioids, and neuropeptide Y. Physiology & Behavior, 107, 699-710. doi:10.1016/j.physbeh.2012.03.004
[108] Bonaventure, P., Nepomuceno, D., Mazur, C., Lord, B., Rudolph, D.A., Jablonoswki, J.A., Carruthers, N.I. and Lovenberg, T.W. (2004) Characterization of N-1-acetyl-2,3-dihydro-1-H-indol-6-yl)-3-(3-cyano-phenyl)-N[1-(2-cyclopentyl-ethyl)-piperidin-4yl]acrylamide (JNJ-5207787), a small molecule antagonist of the neuropeptide Y Y2 receptor. Journal of Pharmacology and Experimental Therapeutics, 308, 1130-1137. doi:10.1124/jpet.103.060459
[109] Gehlert, D.R., Schober, D.A., Beavers, L., Gadski, R., Hoffmann, J.A., Smiley, D.L., Chance, R.E., Lundell, I. and Larhammar, D. (1996) Characterization of the peptide binding requirements for the cloned human pancreatic polypeptide-preferring receptor. Molecular Pharmacology, 50, 112-118.
[110] Flood, J.F. and Morley, J.E. (1989) Dissociation of the effects of neuropeptide Y on feeding and memory: Evidence for pre- and postsynaptic Mediation. Peptides, 10, 963-966. doi:10.1016/0196-9781(89)90176-9
[111] Thorsell, A. (2010) Brain neuropeptide Y and corticotrophin-releasing hormone in mediating stress and anxiety. Experimental Biology and Medicine, 235, 1163-1167. doi:10.1258/ebm.2010.009331
[112] Weinberg, D.H., Sirinathsinghji, J.S., Tan, C.P., Shiao, L.-L., Morin, N., Rigby, M.R., Heavens, R.H., Rapoport, D.R., Bayne, M.L., Cascieri, M.A., Strader, C.D., Linemeyer, D.L. and MacNeil, D.J. (1996) Cloning and expression of a novel neuropeptide Y receptor. Journal of Biological Chemistry, 271, 16435-16438. doi:10.1074/jbc.271.28.16435
[113] Griebel, G. and Holsboer, F. (2012) Neuropeptide recaptor ligands as drugs for psychiatric disease: The end of the beginning? Nature Reviews Drug Discovery, 11, 462-478. doi:10.1038/nrd3702
[114] Minor, R.K., Chang, J.N. and de Cabo, R. (2009) Hungry for life: How the arcuate nucleus and neuropeptide Y may play a critical role in mediating the benefits of calorie restriction. Molecular and Cellular Endocrinology, 299, 79-88. doi:10.1016/j.mce.2008.10.044
[115] Daniels, A.J., Matthews, J., Slepetis, R.J., Jansen, M., Viveros, O.H., Tadapalli, A., Harrington, W., Heyer, D., Landavazo, A., Leban, J.J. and Spaltenstein, A. (1995) High-affinity neuropeptide Y receptor antagonists. Proceedings of the National Academy of Sciences of the United States of America, 92, 9067-9071. doi:10.1073/pnas.92.20.9067
[116] Schober, D.A., Gackenheimer, S.L., Heiman, M.L. and Gehlert, D.R. (2000) Pharmacological characterization of 125I-1229U91 binding to Y1 and Y4 Neuropeptide Y/ peptide YY receptors. Journal of Pharmacology and Experimental Therapeutics, 293, 275-280.
[117] Dumont, Y. and Quirion, R. (2000) [125I]-GR231118: A high affinity radioligand to investigate neuropeptide Y Y1 and YY4receptors. British Journal of Pharmacology, 129, 37-46. doi:10.1038/sj.bjp.0702983
[118] Malmstrom, R.E., Alexandersson, A., Balmer, K.C. and Weilitz, J. (2000) In vivo characterization of the novel neuropeptide Y Y1 receptor antagonist H409/22. Journal of Cardiovascular Pharmacology, 36, 516-525. doi:10.1097/00005344-200010000-00016
[119] Poindexter, G.S., Bruce, M.A., Breitenbucher, J.G., Higgins, M.A., Sit, S.-Y., Romine, J.L., Martin, S.W., Ward, S.A., McGovern, R.T., Clarke, W., Russell, J. and Antal-Zimanyi, I. (2004) Dihydropyridine neuropeptide YY1 receptor antagonist 2: Bioisosteric urea replacement. Bioorganic & Medicinal Chemistry, 12, 507-521. doi:10.1016/j.bmc.2003.10.016
[120] Kameda, M., Ando, M., Nakama, C., Kobayashi, K., Kawamoto, H., Ito, S., Suzuki, T., Tani, T., Ozaki, S., Tokita, S. and Sato, N. (2009) Synthesis and evaluation of a series of 2,4-diaminopyridine derivatives as potential positron emission tomography tracers for neuropeptide Y Y1 receptors. Bioorganic & Medicinal Chemistry Letters, 19, 5124-5127. doi:10.1016/j.bmcl.2009.07.030
[121] Serradeille Gal, C., Lafontan, M., Raufaste, D., Marchand, J., Pouzet, B., Casellas, P., Pascal, M., Maffrand, J.P. and Le Fur, G. (2000) Characterization of NPY receptors controlling lipolysis and leptin secretion in human adipocytes. FEBS Letters, 465, 150-156.
[122] Keller, M., Pop, N., Hutzler, C., Beck-Sickinger, A.G., Bernhardt, G. and Buschauer, A. (2008) Guanidine-acylguanidine bioisosteric approach in the design of radioligands: Synthesis of a tritium-labeled N(G)-propionylar-gininamide ([3H]-UR-MK114) as a highly potent and selective neuropeptide Y Y1 receptor antagonist. Journal of Medicinal Chemistry, 51, 8168-8172. doi:10.1021/jm801018u
[123] Keller, M, Bernhardt, G. and Buschauer, A. (2011) [3H] UR-MK 136: A Highly potent and selective radioligand for neuropeptide YY1 receptors. ChemMedChem, 6, 1566-1571. doi:10.1002/cmdc.201100197
[124] Hostetler, E.D., Sanabria-Bohorquez, S., Fan, H., Zeng, Z., Gantert, L., Williams, M., Miller, P., O’Malley, S., Kameda, M., Ando, M., Sato, N., Ozaki, S., Tokita, S., Ohta, H., Williams, D., Sur, C., Cook, J.J., Burns, H.D. and Hargreaves, R. (2011) Synthesis, characterization, and monkey positron emission tomography (PET) studies of [18F]Y1-973, a PET tracer for the neuropeptide Y Y1 receptor. NeuroImage, 54, 2635-2642. doi:10.1016/j.neuroimage.2010.11.014
[125] Seierstad, M., Bonaventure, P., Dvorak, L., Lord, B., Miller, K.L., Motley, S.T., Nepomuceno, D., Chai, W., Dvorak, C.A., Jablonowski, J. A. , Rudolph, D. A., Shah, C.R., Swanson, D.M., Wong, V.D., Axe, F.U., Lovenberg, T.M. and Carruthers, N.I. (2007) Small molecule Y2 receptor an tagonist: Identification of a novel potent series using pharmacophore-based virtual screening. 23th ACS National Meeting, Boston, 19-23 August 2007, 2009.
[126] Doods, H., Gaida, W., Wieland, H.A., Dollinger, H., Schnorrenberg, G., Esser, F., Engel, E., Eberlein, W. and Rudolf, K. (1999) BIIE0246: A selective and high affinity neuropeptide YY2 receptor antagonist. European Journal of Pharmacology, 384, R3-R5. doi:10.1016/S0014-2999(99)00650-0
[127] Criscione, L., Rigollier, P., Batzl-Hartmann, C., Rueger, H., Stricker-Krongrad, A., Wyss, P., Brunner, L., Whitebread, S., Yamaguchi, Y., Gerald, C., Heurich, R.O., Walker, M.W., Chiesi, M., Schilling, W., Hofbauer K.G., and Levens, N. (1998) Food intake in free-feeding and energy-deprived lean rats is mediated by the neuropeptide Y5 receptor. The Journal of Clinical Investigation, 102, 2136-2145. doi:10.1172/JCI4188
[128] Rueeger, H., Rigollier, P., Yamaguchi, Y., Schmidlin, T., Schilling, W., Criscione, L., Whitebread, S., Chiesi, M., Walker, M.W., Dhanoa, D., Islam, I., Zhang, J. and Gluchowski, C. (2000) Design, synthesis and SAR of a series of 2-substituted 4-amino quinazo-line.neuropeptide Y Y5 receptor antagonists. Bioorganic & Medicinal Chemistry Letters, 10, 1175-1179. doi:10.1016/S0960-894X(00)00177-3
[129] Kanatani, A., Ishihara, A., Iwaasa, M., Nakamura, K., Okamato, O., Hidaka, M., Ho, J., Fukuroda, T., MacNeil, D.J., van der Ploeg, L.H., Ishii, Y., Okabe, T., Fukami, T. and Ihara, M. (2000) L-152,804: Orally active and selective neuropeptide Y Y5 receptor antagonist. Biochemical and Biophysical Research Communications, 272, 169-173. doi:10.1006/bbrc.2000.2696
[130] Nguyen, A.D., Mitchell, N.F., Lin, S., Yulyanigsih, E., Baldock, P.A., Enriquez, R.F., Zhang, L., Shi, Y-C., Zolotukhin, S., Herzog, H. and Sainsbury, A. (2012) Y1 and Y5 receptors are both required for the regulation of food intake and energy homeostasis in mice. PLoS ONE, 7, e40191.
[131] Iida, T., Satoh, H., Maeda, K., Yamamoto, Y., Asakawa, K.-I., Sawada, N., Wada, T., Kadowaki, C., Itoh, T., Mase, T., Weissmann, S.A., Tschaen, D., Krska, S. and Volante, R.P. (2005) Practical synthesis of a new neuropeptide y antagonist via stereoselective addition to a ketene. The Journal of Organic Chemistry, 70, 9222-9229. doi:10.1021/jo0512709
[132] Sakamoto, T., Moriya, M., Haga, Y., Takahashi, T., Shibata, T., Okamoto, O., Nonoshita, K., Kitazawa, H., Hidaka, M., Gomori, A., Iwaasa, H., Ishihara, A., Kanatani, A., Fukami, T., Gao, Y.-D., MacNeil, D.J. and Yang, L. (2009) Identification of novel and orally active spiroindoline NPY Y5 receptor antagonists. Bioorganic & Medicinal Chemistry Letters, 19, 1564-1568. doi:10.1016/j.bmcl.2009.02.035
[133] Tao, Y.-X. (2010) The melanocortin-4 receptor: Physiology, pharmacology and pathophysiology. Endocrine Reviews, 31, 506-543. doi:10.1210/er.2009-0037
[134] Rodriguez, S., Gaunt, T.R., Abdollahi, M.R., Sonnenberg, S. and Day, N.M. (2007) Syndrome: Networks of genotype. Determined feedback loop setpoints. In: Batone, T.E., Ed., Metabolic Syndrome Research Trends, Nova Science Publishers, New York, 2007, pp. 1-63.
[135] Gantz, I., Konda, Y., Tashiro, T., Shimoto, Y., Miwa, H., Munzert, G., Watson, S.J., DelValle, J. and Yamada, T. (1993) Molecular cloning of a melanocortin receptor. The Journal of Biological Chemistry, 268, 8246-8250.
[136] Roselli-Rehfuss, L., Mountjoy, K.G., Robbins, L.S., Mortrud, M.T., Low, M.J., Tatro, J.B., Entwistle, M.L., Simerly, R.B. and Cone, R.D. (1993) Identification of a receptor for gamma melanotropin and other proopiome-lanocortin peptides in the hypothalamus and limbic system. Proceedings of the National Academy of Sciences of the United States of America, 90, 8856-8860. doi:10.1073/pnas.90.19.8856
[137] Mountjoy, K.G., Mortrud, M.T., Low, M.J., Simerly, R.B. and Cone, R.D. (1994) Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Molecular Endocrinology, 8, 1298-1308. doi:10.1210/me.8.10.1298
[138] Mul, J.D., van Boxtel, R., Bergen, D.J.M., Brans, M.A.D., Brakkee, J.H., Toonen, P.W., Garner, K.M., Adan, R. A.H. and Cuppen, E. (2012) Melanocortin receptor 4 deficiency affects body weight regulation, grooming behavior, and substrate preference in the rat. Obesity, 20, 612-621. doi:10.1038/oby.2011.81
[139] Branson, R., Potoczna, N., Kral, J.G., Lentes, K.-U., Hoehe, M.R. and Horber, F.F. (2003) Binge eating as a major phenotype of melanocortin 4 receptor gene mutations. The New England Journal of Medicine, 348, 1096-1103. doi:10.1056/NEJMoa021971
[140] Hinney, A., Bettecken, T., Tarnow, P., Brumm, H., Reichwald, K., Lichtner, P., Scherag, A., Nguyen, T.T., Schlumberger, P., Rief, W., Vollmert, C., Illig, T., Wichmann, H.-E., Schafer, H., Platzer, M., Biebermann, H., Meitinger, T. and Hebebrand, J. (2006) Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative population based sample of obese adults from Germany. The Journal of Clinical Endocrinology & Metabolism, 91, 1761-1769. doi:10.1210/jc.2005-2056
[141] Renè, P, Le Gouill, C., Pogozheva, I.D., Lee, G., Mosberg, H.I., Farooqi, I.S., Valenzano, K.J. and Beuvier, M. (2010) Pharmacological chaperones restore function to MC4R mutants responsible for severe early-onset obesity. Journal of Pharmacology and Experimental Therapeutics, 335, 520-532. doi:10.1124/jpet.110.172098
[142] Mountjoy, K.G. (2010) Functions for pro-opiomelano-cortin-derived peptides in obesity and diabetes. Biochemical Journal, 428, 305-324. doi:10.1042/BJ20091957
[143] Boyce, R.S. and Duhl, D.M. (2004) Melanocortin 4 receptor agonists for the treatment of obesity. Current Opinion in Investigational Drugs, 5, 1063-1071.
[144] Chai, B., Pogozheva, I., Lai, Y., Li, J., Neubig, R., Mosberg, H. and Gantz, I. (2005) Receptor antagonist interactions in the complex of agouti and agouti related protein with human melanocortin 1 and 4 receptors. Biochemistry, 44, 3418-3431. doi:10.1021/bi0478704
[145] McNulty, J.C., Jackson, P.J., Thompson, D.A., Chai, B., Gantz, I., Barsh, G.S., Dawson P.E. and Millhauser, G.L. (2005) Structures of the Agouti signaling protein. Journal of Molecular Biology, 346, 1059-1070. doi:10.1016/j.jmb.2004.12.030
[146] Wolff, G.L., Roberts, D.W. and Mountjoy, K.G. (1999) Physiological consequences of ectopic agouti gene expression: The yellow obese mouse syndrome. Physiological Genomics, 1, 151-163.
[147] Yang, Y., Chen, M., Lai, Y., Gantz, I., Yagmurlu, A., Georgson, K.E. and Harmon, C.M. (2003) Molecular determination of Agouti-related protein binding to human melanocortin-4 receptor. Molecular Pharmacology, 64, 94-103. doi:10.1124/mol.64.1.94
[148] Silverman, A.P., Kariolis, M.S. and. Cochran, J.R. (2011) Cystine-knot peptides engineered with specifities for aIIbβ3 or aIIbβ and avβ3 integrins are potent inhibitors of platelet aggregation. Journal of Molecular Recognition, 24, 127-135. doi:10.1002/jmr.1036
[149] Elias, C.F., Saper, C.B., Maratos-Flier, E.,. Tritos, N.A., Lee, C., Kelly, J., Tatro, J.B., Hoffmann, G.E., Ollmann, M.M., Barsh, G.S., Sakurai, T., Yanagisawa, M. and Elmquist, J.K. (1998) Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area. Journal of Comparative Neurology, 402, 442-459. doi:10.1002/(SICI)1096-9861(19981228)402:4<442::AID-CNE2>3.0.CO;2-R
[150] Biebermann, H., Kühnen, P., Kleinau, G. and Krude, H. (2012) The Neuroendocrine circuit controlled by POMC. MSH, AGRP. In: Joost, H.-G., Ed., Appetite Control, Handbook of Experimental Pharmacology, Springer-Verlag, Berlin, 47-75.
[151] Banno, R., Arima, H., Hayashi, M., Goto, M., Watanabe, M., Sato, I., Ozaki, N., Nagasaki, H., Ozaki, N. and Oiso, Y. (2007) Central administration of melanocortin agonist increased insulin sensitivity in diet-induced obese rats. FEBS Letters, 581, 1131-1136. doi:10.1016/j.febslet.2007.02.019
[152] Chai, B., Li, J.Y., Zhang, W., Wang, H. and Mulholland, M.W. (2009) Melanocortin-4 receptor activation inhibits c-Jun N-terminal kinase activity and promotes insulin signalling. Peptides, 30, 1098-1104. doi:10.1016/j.peptides.2009.03.006
[153] Martin, W.J. and Macintyre, D.E. (2004) Melanocortin receptors and erectile function. European Urology, 45, 706-713. doi:10.1016/j.eururo.2003.03.001
[154] Bednarek, M.A., MacNeil, T., Kalyani, R.N., Tang, R., van der Ploeg, L.H. and Weinberg, D.H. (2001) Selective, high affinity peptide antagonists of alphamelanotropin action at human melanocortin receptor 4: Their synthesis and biological evaluation in vitro. Journal of Medicinal Chemistry, 44, 3665-3672.
[155] Tucci, F.C., White, N.S., Markison, S., Joppa, M., Tran, J. A., Fleck, B.A., Madan, A., Dyck, B.P., Parker, J., Pontillo, J., Arellano, L.M., Marinkovic, D., Jiang, W., Chen, C.W., Gogas, K.R., Goodfellow, V.S., Saunders, J., Foster, A.C. and Chen, C. (2005) Potent and orally active non-peptide antagonists of human melanocortin-4 receptor based on a series of trans-2-disubstituted cyclohexyl-piperazines. Bioorganic & Medicinal Chemistry Letters, 15, 4389-4395. doi:10.1016/j.bmcl.2005.06.071
[156] Tran, J.A., Pontillo, J., Arellano, M., Fleck, B.A., Marinkovic, D., Tucci, F.C., Chen, C.W., Saunders, J., Foster, A.C. and Chen, C. (2005) Structure-activity relationship of a series of cyclohexylpiperidines bearing an amide side chain as antagonists of the human melanocortin-4 receptor. Bioorganic & Medicinal Chemistry Letters, 15, 3434-3438. doi:10.1016/j.bmcl.2005.05.017
[157] Arasasingham, P.N., Fotsch, C., Ouyang, X., Norman, M. H., Kelly, M.G., Stark, K.L., Karbon, B., Hale, C., Baumgartner, J.W., Zambrano, M., Cheetham, J. and Tamayo, N.A. (2003) Structure-activity relationship of (1-aryl-2-piperazinylethyl)piperazines: Antagonists for the AGRP/ melanocortin receptor binding. Journal of Medicinal Chemistry, 46, 9-11. doi:10.1021/jm0255522
[158] Douglass, J., McKinzie, A.A. and Couceyro, P. (1995) PCR differential display identifies a rat brain mRNA that is transcriptionally regulated by cocaine and amphetamine. The Journal of Neuroscience, 15, 2471-2481.
[159] Rogge, G., Jones, D., Hubert, G.W., Lin, Y. and Kuhar, M.J. (2008) CART peptides: Regulators of body weight, reward and other functions. Nature Reviews Neuroscience, 9, 747-758. doi:10.1038/nrn2493
[160] Lakatos, A., Prinster, S., Vicentic, A., Hall, R. and Kuhar, M.J. (2005) Cocaine-and amphetamine-regulated transcript (CART) peptide activates the extracellular signal-regulated kinase (ERK) pathway in AtT20 cells via putative G-protein coupled receptors. Neuroscience Letters, 384, 198-202. doi:10.1016/j.neulet.2005.04.072
[161] Jones, D.J. and Kuhar, M.J. (2008) CART receptor binding in primary cell culture of rat nucleus accumbens. Synapse, 62, 122-127. doi:10.1002/syn.20476
[162] Maletinska, L., Maixnerova, J., Matyskova, R., Haugvicova, R., Sloncova, E., Elbert, T., Slaninova, J. and Zelezna, B. (2007) Cocaine- and amphetamine-regulated transcript (CART) peptide specific binding in pheochromocytoma cells PC12. European Journal of Pharmacology, 559, 109-114. doi:10.1016/j.ejphar.2006.12.014
[163] Kastin, A. and Akerstrom, V. (1999) Entry of CART into brain is rapid but not inhibited by excess CART or leptin. American Journal of Physiology, 277, E901-E904.
[164] Del Guidice, E.M., Santoro, N., Cirillo, G., D’Urso, L., Di Toro, R. and Perrone, L. (2001) Mutational screening of the CART gene in obese children: Identifying a mutation (Leu34Phe) associated with reduced resting energy expediture and co-segregating with obesity phenotype in a large family. Diabetes, 50, 2157-2160. doi:10.2337/diabetes.50.9.2157
[165] Hunter, R.G., Philpot, K., Vicentic, A., Dominguez, G., Hubert, G.W. and Kuhar, M.J. (2004) CART in feeding and obesity. Trends in Endocrinology & Metabolism, 15, 454-459. doi:10.1016/S1043-2760(04)00220-6
[166] Lin, Y., Hall, R.A. and Kuhar, M.J. (2011) CART peptide stimulation of G-protein-mediated signalling in differentiated PC12 cells: Identification of PACAP 6-38 as a CART receptor antagonist. Neuropeptides, 45, 351-358 doi:10.1016/j.npep.2011.07.006
[167] Sakurai, T., Amemiya, A., Ishii, M., Matsuzaki, I., Chemelli, R.M., Tanaka, H., Williams, H.C., Richardson, J.A., Kozlowski, G.P., Wilson, S., Arch, J.R., Buckingham, R.E., Haynes, A.C., Carr, S.A., Annan, R.S., McNulty, D.E., Liu, W.S., Terrett, J.A., Elsbourbagy, N.A., Bergsma, D.J. and Yanasigawa, M. (1998) Orexins and orexin receptors: A family of hypothalamic neuropeptides and G-protein coupled receptors that regulate feeding behaviour. Cell, 92, 573-585. doi:10.1016/S0092-8674(00)80949-6
[168] De Lecea, L. and Sutcliffe, J.G. (1999) The hypocretins/ orexins: Novel hypothalamic neuropeptides involved in different physiological systems. Cellular and Molecular Life Sciences, 56, 473-480. doi:10.1007/s000180050446
[169] Spinazzi, R., Andreis, P.G., Rossi, G.P. and Nussdorfer, G.G. (2006) Orexins in the regulation of the hypothalamic-pituitary-adrenal-axis. Pharmacological Reviews, 58, 46-57. doi:10.1124/pr.58.1.4
[170] Kilduff , T.S. and Peyron, C. (2000) The hyocretin/orexin ligand-receptor system: Implications for sleep and sleep disorders. Trends in Neurosciences, 23, 359-365. doi:10.1016/S0166-2236(00)01594-0
[171] Espana, R.A. and Scammell, T.E. (2004) Sleep neurobiology for the clinician. Sleep, 27, 811-820.
[172] Tsujino, N. and Sakurai, T. (2009) Orexin/hypocretin: A neuropeptide at the interface of sleep, energy homeostasis, and reward system. Pharmacological Reviews, 61, 162-176. doi:10.1124/pr.109.001321
[173] Bagdoyan, H.A. and Lydic, R. (2012) The neurochemistry of sleep and wakefulness in. In: Brady, T., Siegel, G.J., Albers, R.W. and Price, D.L., Eds., Basic Neurochemistry, 8th Edition, Elsevier, Amsterdam, 982-999.
[174] Overeem, S., Lammers, G.J. and Tafti, M. (2007) Disorders of sleep and circadian rhythm. In: Waxman, S.G., Ed., Molecular Neurology, Elsevier, Academic Press, Burlington, San Diego, London, 409-426.
[175] Foutz, A.S., Mitler, M.M., Cavalli-Sforza, L.L., Dement, W.C. (1979) Genetic factors in canine narcolepsy. Sleep, 1, 413-421.
[176] Baker, T.L. (1985) Sleep apnea disorders. Introduction to sleep and sleep disorders. Medical Clinics of North America, 69, 1123-1152.
[177] Lin, L., Faraco, F., Li, R., Kadotani, H., Rogers, W., Lin, X., Qiu, X., de Jong, P.J., Nishino, S. and Mignot, E. (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin receptor 2 gene. Cell, 98, 365-376. doi:10.1016/S0092-8674(00)81965-0
[178] Nishino, S., Ripley, B., Overeem, S., Nevsimalova, S., Lammers, G.J., Vankova, J., Okun, M., Rogers, W., Brooks, S. and Mignot, E. (2001) Low cerebrospinal fluid hypocretin (orexin) and altered energy homeostasis in human narcolepsy. Annals of Neurology, 50, 381-388. doi:10.1002/ana.1130
[179] Ripley, B., Overeem, S., Fujiki, N., Nevsimalova, S., Uchino, M., Yesavage, J., Di Monte, D., Dohi, K., Melberg, A., Lammers, G.J., Nishida, Y., Roelandse, F. W.C., Hungs, M., Mignot, E. and Nishino, S. (2001) CSF hypocretin/orexin levels in narcolepsy and other neurological conditions. Neurology, 57, 2253-2258. doi:10.1212/WNL.57.12.2253
[180] Scammell, T.E. and Winrow, C. (2011) Orexin receptors: Pharmacology and therapeutic opportunities. Annual Review of Pharmacology and Toxicology, 51, 243-266. doi:10.1146/annurev-pharmtox-010510-100528
[181] Holmqvist, T., Johansson, L., Ostman, M., Ammoun, S., Akerman, K.E. and Kukkonen, J.P. (2005) OX1 orexin receptor couple to adenylyl cyclase regulation via multiple mechanisms. The Journal of Biological Chemistry, 280, 6570-6579. doi:10.1074/jbc.M407397200
[182] Faedo, S., Perdona, E., Antolini, M., di Fabio, R., Pich, E.M. and Corsi, M. (2012) Functional and binding kinetic studies make a distinction between OX1 and OX2 orexin receptor antagonists. European Journal of Pharmacology, 692, 1-9.
[183] Heifetz, A., Morris, G.B., Biggin, P.C., Barker, O., Fryatt, T., Bentley, J., Hallett, D., Manikowski, D., Pal, S., Reifegerste, R., Slack, M. and Law, R. (2012) Study of human orexin-1 and -2 G-protein-coupled receptors with novel and published antagonists by modeling, molecular dynamics simulation, and site-directed mutagenesis. Biochemistry, 51, 3178-3197. doi:10.1021/bi300136h
[184] Whitman, D.B., Cox, C.D., Breslin, M.J., Brashear, K.M., Schreier, J.D., Bogusky, M.J., Bednar, R.A., Lemaire, W., Bruno, J.G., Hartman, G.D., Reiss, D.R., Harrell, C.M., Kraus, R.L., Li, Y., Garson, S.L., Doran, S.M., Prueksaritanont, T., Li, C., Winrow, C.J., Koblan, K.S., Renger, J.J. and Coleman, P.J. (2009) Discovery of a potent CNS penetrant orexin receptor antagonist based on an N,Ndisubstituted-1,4-diazepane scaffold that promotes sleep in rats. ChemMedChem, 4, 1069-1074. doi:10.1002/cmdc.200900069
[185] Haynes, A.C., Jackson, B., Chapman, H., Tadayyon, M., Johns, A., Porter, R.A. and Arch, J.R. (2000) A selective orexin-1 receptor antagonist reduces food consumption in male and female rats. Regulatory Peptides, 96, 45-51. doi:10.1016/S0167-0115(00)00199-3
[186] Putula, J. and Kukkonen, J.P. (2012) Mapping of the binding sites for OX1 orexin receptor antagonist, SB-334867, using orexin/hypocretin receptor chimaeras. Neuroscience Letters, 506, 111-115. doi:10.1016/j.neulet.2011.10.061
[187] Malherbe, P., Borroni, E., Gobbi, L., Knust, H., Nettenkoven, M., Pinard, E., Roche, O., Roger Evans, M., Wettstein, J.G. and Moreau,, J.-L. (2009) Biochemical and behavioral characterization of EMPA, a novel high-affinity, selective antagonist for the OX2 receptor. British Journal of Pharmacology, 156, 1326-1341. doi:10.1111/j.1476-5381.2009.00127.x
[188] Nagasaki, H., Chung, S., Dooley, C.T., Wang, Z., Li, C., Saito, Y., Clark, S.D., Houghten, R.A. and Civelli, O. (2009) The pharmacological properties of a novel MCH1 receptor antagonist isolated from combinatorial libraries. European Journal of Pharmacology, 602, 194-202. doi:10.1016/j.ejphar.2008.10.068
[189] Kawauchi, H., Kawazoe, I., Tsubokawa, M., Kishida, M., and Baker, B.I. (1983) Characterization of melanin-concentrating hormone in chum salmon pituitaries. Nature, 305, 321-323. doi:10.1038/305321a0
[190] Pissios, P., Ozcan, U., Kokkotou, T., Liew, C.W., Liu, S., Peters, J.N., Dahlgren, G., Karamchandani, J., Kudva, Y. C., Kurpad, A.J., Kennedy, R.T., Marathos-Flier, E. and Kulkarni, R.N. (2007) Melanin-concentrating hormone is anovel regulator of islet function and growth. Diabetes, 56, 311-319. doi:10.2337/db06-0708
[191] Shimada, M., Tritos, N.A., Lowell, B.B., Flier, J.S. and Maratos-Flier, E. (1998) Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature, 396, 670-674. doi:10.1038/25341
[192] Kreienkamp, D.H., Weise, C., Buck, F. and Richter, D. (1999) Identification of melanin concentrating hormone as the natural ligand for the orphan somatostatin-like receptor (SLC-1). FEBS Letters, 457, 522-524. doi:10.1016/S0014-5793(99)01092-3
[193] Chambers, J., Ames, R.S., Bergsma, D., Muir, A., Fitzgerald, L.R., Hervieu, G., Dytko, G.M., Foley, J.J., Martin, J., Liu, W.S., Park, J., Ellis, C., Gangully, S., Konchar, S., Cluderay, J., Leslie, R., Wilson, S. and Sarau, H.M. (1999) Melanin concentrating hormone ist the cognate ligand for the orphan G-protein coupled receptor SLC-1. Nature, 400, 261-265. doi:10.1038/22313
[194] Lembo, P.M., Grazzini, E., Cao, J., Hubatsch, D.A., Pelletier, M., Hoffert, C., Stonge, S., Pou, C., Labrecque, J., Groblewski, T., O’Donnell, O., Payza, K., Ahmad, S. and Walker, P. (1999) The receptor for the orexigenic peptide melanine concentrating hormone in a G-protein coupled receptor. Nature Cell Biology, 1, 267-271. doi:10.1038/12978
[195] Saito, Y., Nothacker, H.P., Wang, Z, Lin, S.H., Leslie, F. and Civelli, O. (1999) Molecular characterization of the melanin-concentrating-hormone receptor. Nature, 400, 265-269. doi:10.1038/22321
[196] Saito, Y. and Nagasaki, H. (2008) The melanin-concentrating hormone system and its physiological function. In: Civelli, O. and Zhou, Q.-Y., Eds., Results and Problems in Cell Differentiation (46) Orphan G-Protein Coupled Receptors and Novel Neuropeptides, Springer-Verlag, Berlin, 159-176. doi:10.1007/400_2007_052
[197] Chung, S., Parks, G.S., Lee, C. and Civelli, O. (2011) Recent updates on the melanin-concentrating hormone (MCH) and its receptor system: Lessons from MCH1R antagonists. Journal of Molecular Neuroscience, 43, 115-121. doi:10.1007/s12031-010-9411-4
[198] Saito, Y., Cheng, M., Leslie, F.M. and Civelli, O. (2001) Expression of the melanin-concentrating hormone (MCH) receptor mRNA in the rat brain. Journal of Comparative Neurology, 435, 26-40. doi:10.1002/cne.1191
[199] Kokkotou, E.G., Tritos, N.A., Mastaitis, J.W., Slieker, L., and Maratos-Flier, E. (2001) Melanin concentrating hormone receptor is a target of leptin action in the mouse brain. Endocrinology, 142, 680-686. doi:10.1210/en.142.2.680
[200] Wermter, A.-K., Reichwald, K., Büch, T., Geller, F., Platzer, C., Huse, K., Hess, C., Remschmidt, H., Gudermann, T., Preibisch, G., Siegfried, W., Goldschmidt, H.-P., Li, W.-D., Price, R.A., Biebermann, H., Krude, H., Vollmert, C., Wichmann, H.E., Illig, T., Sorensen, T.I., Astrup, A., Hingstrup Larsen, L., Pedersen, O., Eberle, D., Clement, K., Blundell, J., Wabitsch, M., Schafer, H., Platzer, M., Hinney, A. and Hebebrand, J. (2005) Mutation analysis of the MCHR1 gene in human obesity. European Journal of Endocrinology, 152, 851-862. doi:10.1530/eje.1.01917
[201] Hill, J., Duckworth, M., Murdock, P., Rennie, G., Sabido-David, C., Ames, R.S., Szekeres, P., Wilson, S., Bergsma, D.J., Gloger, I.S., Levy, D.S., Chambers, J.K. and Muir, A.I. (2001) Molecular cloning and functional characterization of MCH2, a novel human MCH receptor. The Journal of Biological Chemistry, 276, 20125-20129. doi:10.1074/jbc.M102068200
[202] Sailer, A.W., Sano, H., Zeng, Z., McDonald, T.P., Pong, S.S., Feighner, S.D., Tan, C.P., Fukami, T., Iwaasa, H., Hreniuk, D.L., Morin, N.R., Sadowski, S.J., Ito, M., Bansal., A., Ky, B., Figueroa, D.J., Jiang, Q., Austin, C.P., MacNeil, D.J., Ishihara, A., Ihara, M., Kanatani, A., van der Ploeg, L.H., Howard, A.D. and Liu, Q. (2001) Identification and characterization of a second melanin-concentrating hormone receptor, MCH-2R. Proceedings of the National Academy of Sciences of the United States of America, 98, 7564-7569. doi:10.1073/pnas.121170598
[203] Hawes, B.E., Green, B., O’Neill, K., Fried, S. and Graziano, M. P. (2000) The melanin-concentrating hormone couples to multiple tG protein to activate diverse intracellular signaling pathways. Endocrinology, 141, 4524-4532. doi:10.1210/en.141.12.4524
[204] An, S., Cutler, G., Zhao, J.J., Huang, S.-G., Tian, H., Li, W., Liang, L., Rich, M., Bakleh, A., Du, J, Chen, J.-L. and Dai, K. (2001) Identification and characterization of a melanin concentrating hormone receptor. Proceedings of the National Academy of Sciences of the United States of America, 98, 7576-7581. doi:10.1073/pnas.131200698
[205] Mihalic, J.T., Chen, X., Fan, P., Chen, X., Fu, Y., Liang, L., Reed, M., Tang, L., Chen, J.-L., Jaen, J., Li, L. and Dai, K. (2011) Discovery of a novel series of melanin-concentrating hormone receptor 1 antagonists for the treatment of obesity. Bioorganic & Medicinal Chemistry Letters, 21, 7001-7005. doi:10.1016/j.bmcl.2011.09.110
[206] Hervieu, G.I., Cluderay, J.E., Harrison, D., Meakin, J., Maycox, P., Nasir, S. and Leslie, R.A. (2000) The distribution of the mRNA and protein products of the melanin concentrating hormone receptor gene, slc-1, in the central nervous system of the rat. European Journal of Neuroscience, 12, 1194-1216. doi:10.1046/j.1460-9568.2000.00008.x
[207] Mori, M., Harada, M., Terao, Y., Sugo, T., Watanabe, T., Shimomura, Y., Abe, M., Shintani, Y., Onda, H., Nishimura, O. and Fujino, M. (2001) Cloning of a novel G protein coupled receptor, SLT, a subtype of melanin-concentrating hormone receptor. Biochemical and Biophysical Research Communications, 283, 1013-1018. doi:10.1006/bbrc.2001.4893
[208] Qu, D., Ludwig, D.S., Gammeltoft, S., Piper, M., Pelleymounter, M.A., Cullen, M.J., Mathes, W.F., Przypek, J., Kanarek, R. and Maratos-Flier, E. (1996) A role for melanin concentrating hormone in the central regulation of feeding behaviour. Nature, 380, 243-247. doi:10.1038/380243a0
[209] Ludwig, D.S., Mountjoy, K.G., Tatro, J.B., Gilette, J.A., Frederich, R.C., Flier, J.S. and Maratos-Flier, E. (1998) Melanin-concentrating hormone: A functional melanoortin antagonist in the hypothalamus. Endocrinology and Metabolism: American Journal of Physiology, 274, E627-E633.
[210] Alon, T. and Friedman, J.M. (2006) Late-onset leaness in mice with targeted ablation of melanin concentrating hormone neurons. The Journal of Neuroscience, 26, 389-397. doi:10.1523/JNEUROSCI.1203-05.2006
[211] Mendez-Andino, J.L. and Wos, J.A. (2007) MCHR1 antagonists: What is keeping most research programs away from the clinic. Drug Discovery Today, 12, 972-979. doi:10.1016/j.drudis.2007.08.010
[212] Andersen, D., Storz, T., Liu, P., Wang, X., Li, L., Fan, P., Chen, X., Allgeier, A., Burgos, A., Tedrow, J., Baum, J., Chen, Y., Crockett, R., Huang, L., Syed, R., Larsen, R.D. and Martinelli, M.J. (2007) Stereoselective synthesis of a MCH1R antagonist. The Journal of Organic Chemistry, 72, 9648-9655. doi:10.1021/jo701894v
[213] Rokosz, L.L. (2007) Discovery and development of melanin-concentrating hormone receptor 1 antagonists for the treatment of obesity. Expert Opinion on Drug Discovery, 2, 1301-1327. doi:10.1517/17460441.2.10.1301
[214] Gehlert, D.R., Rasmussen, K., Shaw, J., Li, X., Ardayfio, P., Craft, L., Coskun, T., Zhang, H.Y., Chen, Y. and Witkin, J.M. (2009) Preclinical evaluation of melanin-concentrating hormone receptor 1 antagonism for the treatment of obesity and depression. Journal of Pharmacology and Experimental Therapeutics, 329, 429-438.
[215] Chaki, S., Funakoshi, T., Hirota-Okuno, S., Nishiguchi, M., Shimazaki, Iijima, M., Grottick, A.J., Kanuma, K., Omodera, K., Sekiguchi, Y., Okuyama, S., Tran, T.-A., Semple, G. and Thomsen, W. (2005) Anxiolytic- and antidepressant-like profile of ATC0065 and ATC0175: Nonpeptidic and orally active melanin-concentrating hormone receptor 1 antagonists. Journal of Pharmacology and Experimental Therapeutics, 313, 831-839. doi:10.1124/jpet.104.081711
[216] Sasmal, P.K., Sasmal, S., Rao, P.T., Venkatesham, B., Roshaiah, M., Abbineni, C., Khanna, I., Jadhav, V.P., Suresh, J., Talwar, R., Muzeeb, S., Receveur, J.M., Frimurer, T.M., Rist, O., Elster, L. and Hogberg, T. (2010) Discovery of novel, orally available benzimidazoles as melanin concentrating hormone receptor 1 (MCHR1) antagonists. Bioorganic & Medicinal Chemistry Letters, 20, 5443-5448. doi:10.1016/j.bmcl.2010.07.086
[217] Sasmal, P.K., Sasmal, S., Abbineni, C., Venkatesham, B., Rao, P.T., Roshaiah, M., Khanna, I., Sebastian, V.J., Suresh, J., Singh, M., Talwar, R., Shashikumar, D., Reddy, K.H., Frimurer, T.M., Rist, O., Elster, L. and Hogberg, T. (2011) Synthesis and SAR studies of benzimidazol derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists focus to detune hERG inhibition. MedChemComm, 2, 385-389. doi:10.1039/c1md00015b
[218] Sasmal, S., Balaji, G., Kanna Reddy, H.R., Balasubrahanyam, D., Srinivas, G., Kyasa, S.K., Khanna, I., Talwar, R., Suresh, J., Jadhav, V.P., Muzeeb, S., Shashikumar, D., Harinder Reddy, K., Sebastian, V.J., Frimurer, T.M., Rist, O., Elster, L. and Hogberg, T.D., (2012) Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists. Bioorganic & Medicinal Chemistry Letters, 22, 3157-3162. doi:10.1016/j.bmcl.2012.03.050
[219] Samal, S., Balasubrahmanyam, D., Kanna Reddy, H.R., Balaji, G., Srinivas, G., Cheera, S., Abbineni, C., Sasmal, I., Khanna, P.K., Sebastian, V.J., Jahav, V., Singh, M.P., Talwar, R., Suresh, J., Shashikumar, D., Reddy, K.H., Shihorkar, V., Frimurer, T.M., Rist, O., Elster, K. and Hogberg, T. (2012) Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonist: Part 2. Bioorganic & Medicinal Chemistry Letters, 22, 3163-3167. doi:10.1016/j.bmcl.2012.03.049
[220] Iyengar, R.R., Lynch, J.K., Mulhern, M.M., Judd, A.S., Freeman, J.C., Gao, J., Souers, A.J., Zhao, G., Wodka, D., Falls, H.D., Brodjian, S., Dayton, B.D., Reilly, R.M., Swanson, S., Su, Z., Martzin, R.L., Leitza, S.T., Houseman, K.A., Diaz, G., Collins, C.A., Sham, H.L. and Kym, P.R. (2007) An evaluation of 3,4-methylenedioxy phenyl replacements in the aminoperidine chromone class of MCHr1 antagonists. Bioorganic & Medicinal Chemistry Letters, 17, 874-878. doi:10.1016/j.bmcl.2006.11.065
[221] Su, J., Tang, H., McKittrick, B.A., Gu, H., Guo, T., Qian, G., Burnett, D.A., Clader, J.W., Greenlee, W.J., Hawes, B.E., O’Neill, K., Spar, B., Weig, B., Kowalski, T. and Sorota, S. (2007) Synthesis of novel bicycle [4.1.0] heptanes and bicycle[3.1.0]hexane derivatives as melaninconcentrating hormone receptor R1 anatgonists. Bioorganic & Medicinal Chemistry Letters, 17, 4845-4850. doi:10.1016/j.bmcl.2007.06.048
[222] Ando, M., Sekino, E., Haga, Y., Moriya, M., Ito, M., Ito, J., Iwaasa, H., Ishihara, A., Kanatani, A. and Ohtake, N. (2009) Discovery of novel phenethylpyridone derivatives as potent melanin-concentrating hormone 1 receptor antagonists. Bioorganic & Medicinal Chemistry Letters, 19, 5186-5190. doi:10.1016/j.bmcl.2009.07.023
[223] Kasai, Kamaura, M., Kamata, M., Aso, K., Ogino, H., Nakano, Y., Watanabe, K., Kaisho, T, Tawada, M., Nagisa, Y., Takekawa, S., Kato, K., Suzuki, N. and Ishihara, Y. (2011) Melanin-concentrating hormone receptor 1 anagonists: Synthesis, structure-activity relationship, docking studies. Bioorganic & Medicinal Chemistry, 19, 6261-6273. doi:10.1016/j.bmc.2011.09.007
[224] Johansson A. (2011) Recent progress in the discovery of melanin-concentrating hormone 1-receptor antagonists. Expert Opinion on Therapeutic Patents, 21, 905-925. doi:10.1517/13543776.2011.575063
[225] Luthin, D.R. (2007) Anti-obesity effects of small molecule melanin-concentrating hormone receptor1 (MCHR1) antagonists. Life Sciences, 81, 423-440. doi:10.1016/j.lfs.2007.05.029
[226] Recanatini, M., Poluzzi, E., Masetti, M., Cavalli, A. and De Ponti, F. (2005) QT prolongation through hERG K+ channel blockade: Current knowledge and strategies for the early prediction during drug development. Medicinal Research Reviews, 25, 133-166.
[227] Sanguinetti, M.C. and Tristani-Firouzi, M. (2006) hERG potassium channels and cardiac arrhythmia. Nature, 440, 463-469. doi:10.1038/nature04710
[228] Suzuki, T., Kameda, M., Ando, M., Mayazoe, H., Sekino, E., Ito, S., Masutani, K., Kamijo, K., Takezawa, A., Moriya, M., Ito, M., Ito, J., Nakase, K., Matsushita, H., Ishihara, A., Takenaga, N., Tokita, S., Kanatani, A., Sato, N. and Fukami, T. (2009) Disvovery of novel diarylketoxime derivatives as selective and orally active melanin-concentrating hormone 1 receptor antagonists. Bioorganic & Medicinal Chemistry Letters, 19, 5339-5345. doi:10.1016/j.bmcl.2009.07.132
[229] Suzuki, T., Moriya, M., Sakamoto, T., Suga, T., Kishino, H., Takahashi, H., Ishikawa, M., Nagai, K., Imai, Y., Sekino, E., Ito, M., Iwaasa, H., Ishihara, A., Tokita, S., Kanati, A., Sato, N. and Fukami, T. (2009) Discovery of novel spiro-piperidine derivatives as highly potent and selective melanin-concentrating hormone 1 receptor antagonists. Bioorganic & Medicinal Chemistry Letters, 19, 3072-3077. doi:10.1016/j.bmcl.2009.04.016
[230] Mihalic, J.T., Fan, P., Chen, X., Fu, Y., Motani, A., Liu, L., Liang, L., Lindstrom, M., Tang, L., Chen, J.-L., Jaen, J., Dai, K. and Li, L. (2012) Discovery of a novel melanin-concentrating hormone receptor 1 (MCHR1) antagonist with reduced hERG inhibition. Bioorganic & Medicinal Chemistry Letters, 22, 3781-3785. doi:10.1016/j.bmcl.2012.04.006
[231] Souers, A.J , Wodka, D., Gao, J., Lewis, J.C., Vasudevan, A., Gentles, R., Brodjian, S., Dayton, B., Ogiela, C.A., Fry, D., Hernandez, L.E., Marsh, K.C., Collins, C.A. and Kym, P.R. (2004) Synthesis and evaluation of 2-amino-8-alkoxy quinolines as MCHR1 antagonists, Part 1. Bioorganic & Medicinal Chemistry Letters, 14, 4873-4877. doi:10.1016/j.bmcl.2004.07.032
[232] Souers, A.J., Iyengar, R.R., Judd, A.S., Gao, J., Zhao, G., Brune, M.E., Napier, J.J., Mulhern, M.M., Lynch, J.K., Freeman, J.C., Wodka, D., Chen, C.J., Falls, H.D., Brodjian, S., Dayton, B.D., Diaz, G.J., Bush, E.N., Shapiro, R., Droz, B.A., Knourek-Segel, V., Hernandez, L.E., Marsh, K.C., Reilly, R.M., Sham, H.L., Collins, C.A. and Kym, P.R. (2007) Constrained 7-fluorocarbochromone-4-aminopiperidine based melanin-concentrating hormone recaptor 1 antagonists. The effects of chirality on substituted indan-1-ylamines. Bioorganic & Medicinal Chemistry Letters, 17, 884-889. doi:10.1016/j.bmcl.2006.11.061
[233] Vasudevan, A., Wodka, D., Verzal, M.K., Souers, A.J., Gao, J., Brodjian, S., Fry, D., Dayton, B., Marsh, K.C., Hernandez, L.E., Ogiela, C.A., Collins C. A. and Kym, P.R. (2004) Synthesis and evaluation of 2-amino-8-alkoxy quinolins as MCHR1antagonists. Part 2. Bioorganic & Medicinal Chemistry Letters, 14, 4879-4882. doi:10.1016/j.bmcl.2004.07.034
[234] Vasudevan, A., Verzal, M.K., Wodka, D., Souers, A.J., Blackburn, C., Che, J.L., Lai, S., Brodjian, S., Falls, D.H., Dayton, B.D., Govek, E., Daniels, T., Geddes, B., Marsh, K.C. Hernandez, L.E., Collins, C.A. and Kym, P.R. (2005) Identification of aminopiperidine benzamides as MCHR1 antagonists. Bioorganic & Medicinal Chemistry Letters, 15, 3412-3416. doi:10.1016/j.bmcl.2005.05.023
[235] Borowsky, B., Durkin, M.M., Ogozalek, K., Marzabadi, M.R., De Leon, J., Lagu, B., Heurich, R., L.ichtblau, H., Shaposhnik, Z., Daniewska, I., Blackburn, T.P., Branchek, T.A., Gerald, C., Vaysse, P.J. and Forray, C. (2002) Antidepressant, anxiolytic an anorectic effects of a melanin-concentrating hormone-1 receptor antagonist. Nature Medicine, 8, 825-830.
[236] David, D.J., Klemenhagen, K.C., Holick, K.A., Saxe, M.D., Mendez, I., Santarelli, L., Craig, D.A., Zhong, H., Swanson, C.J., Hegde, L.G., Ping, X.L., Dong, D., Marzabadi, M.R., Gerald, C.P. and Hen, R. (2007) Efficacy of the MCHR1 antagonist N-[3-(1-{[4-(3,4-difluoro-phenoxy) phenyl]methyl}(4-piperidyl))-4-methylphenyl]-2-methylpropanamide (SNAP 94847) in mouse models of anxiety and depression following acute and chronic administration is independent of hippocampal neurogenesis. Journal of Pharmacology and Experimental Therapeutics, 321, 237-248. doi:10.1124/jpet.106.109678
[237] Chen, X., Mihalic, J., Fan, P., Liang, L., Lindstrom, M., Wong, S., Ye, Q., Fu, Y., Jaen, J., Chen, J.-L., Dai, K. and Li, L. (2012) Discovery and characterization of a potent and selective antagonist of melanin-concentrating hormone receptor. Bioorganic & Medicinal Chemistry Letters, 22, 363-366. doi:10.1016/j.bmcl.2011.10.125
[238] Statnick, M.A., Schober, D.A., Mayne, N.G., Burnett, J.P. and Gehlert, D.R. (1997) Analysis of NPY receptor subtypes in the human frontal cortex reveals abundant Y1 mRNA and binding sites. Peptides, 18, 137-143. doi:10.1016/S0196-9781(96)00246-X
[239] Irani, B.G., Dunn-Meynell, A.A. and Levin, B.E. (2006) Altered hypothalamic leptin, insulin, and melanocortin binding associated with moderate-fat diet and predisposetion to obesity. Endocrinology, 148, 310-316. doi:10.1210/en.2006-1126
[240] Audinot, V., Lahaye, S., Beauverger, P., Rodriguez, M., Galizzi, J.P., Fauchere, J.L. and Boutin, J.A. (2001) [125I]-S36057: A new and highly potent radioligand for the melanin-concentrating hormone receptor. British Journal of Pharmacology, 133, 371-378. doi:10.1038/sj.bjp.0704085
[241] Arai, K., Ohata, H. and Shibasaki, T. (1998) Non-peptidic corticotrophin-releasing hormone receptor type 1 antago-nist reverses restraint stress-induced shortening of sodium pentobarbital-induced sleeping time of rats: Evidence that an increase in arousal induced by stress is mediated through CRH receptor type 1. Neuroscience Letters, 255, 103-106. doi:10.1016/S0304-3940(98)00719-8
[242] McCarthy, J.R., Heinrichs, S.C. and Grigoriadis, D.E. (1999) Recent advances with the CRF1 receptor: Design of small molecule inhibitors, receptor subtypes and clini-cal indications. Current Pharmaceutical Design, 5, 289-315.
[243] Jagoda, E., Contoreggi, C., Lee, M.J., Kao, C.H., Szajek, L.P., Listwak, S., Gold, P., Chrousos, G., Greiner, E., Kim, B.M., Jacobson, A.E., Rice, K.C. and Eckelman, W. (2003) Autoradiographic visualization of corticotrophin releasing hormone type 1 receptors with a nonpeptide ligand: synthesis of [76Br]MJL-1-109-2. Journal of Medicinal Chemistry, 46, 3559-3562. doi:10.1021/jm034077k
[244] Chen, C., Dagnino Jr., R., De Souza, E.B., Grigoriadis, D.E., Huang, C.Q., Kim, K.I., Liu, Z., Moran, T., Webb, T.R., Whitten, J.P., Xie,Y.F. and McCarthy, J.R. (1996) Design and synthesis of a series of non-peptide highaffinity human corticotropin-releasing factor1 receptor antagonists. Journal of Medicinal Chemistry, 39, 4358-4360. doi:10.1021/jm960149e
[245] Whitten, J.P., Xie, Y.F., Erickson, P.E., Webb, T.R., DeSouza, E.B., Grigoriadis, D.E. and McCarthy, J.R. (1996) Rapid microscale synthesis, a new method for lead optimization using robotics and solution phase chemistry: Application to the synthesis and optimization of corticotropin releasing factor 1 receptor antagonists. Journal of Medicinal Chemistry, 39, 4354-4357. doi:10.1021/jm960148m
[246] Griebel, G., Perrault, G. and Sanger, D.J. (1998) Characterization of the behavioral profile of the non-peptide CRF receptor antagonist CP-154,526 in anxiety models in rodents. Comparison with diazepam and buspirone. Psychopharmacology, 138, 55-66. doi:10.1007/s002130050645
[247] Erondu, N., Wadden, T., Gantz, I, Musser, B., Nguyen, A.M., Bays, H., Bray, G., O’Neil, P.M.O., Basdevant, A., Kaufman, K.D., Heymsfield, S.B., Amatruda, J.M. (2007) Effect of NPY5R antagonist MK-0557 on weight regain after very-low-calorie diet-induced weight loss. Obesity, 15, 895-905. doi:10.1038/oby.2007.620
[248] Chaki, S., Hirota, S., Funakoshi, T., Suzuki, Y., Suetake, S., Okubo, T., Ishii, T., Nakazato, A. and Okuyama,S. (2003) Anxiolytic-like and antidepressant-like activities of MCL0129 (1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl-)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl] piperazine), a novel and potentnonpeptide antagonist of the melanocortin-4 receptor. Journal of Pharmacology and Experimental Therapeutics, 304, 818-826. doi:10.1124/jpet.102.044826
[249] Kato, K., Terauchi, J., Mori, M., Suzuki, N., Shimomura, Y., Takekawa, S. and Ishihara, Y. (2001) Melanin concentrating hormone antagonist. PCT Application. WO/ 2001/021577. Takeda Chemical Industries, Ltd., March 29.
[250] Okoyuma, S., Chaki, S., Kawashima, N., Suzuki, Y., Ogawa, S.-I., Nakazato, A., Kumagai, T., Okubo, T. and Tomisawa, K. (1999) Receptor binding, behavioral and electrophysiological profiles of nonpeptide corticotropin-releasing factor subtype 1 receptor antagonists CRA1000 and CRA1001. Journal of Pharmacology and Experimental Therapeutics, 289, 926-935.
[251] Vidarsdottir, S., Smeets, P.A.M., Eichelsheim, D.L., van Osch, M.J.P., Viergever, M.A., Romijn, J.A., van der Grond, J. and Pijl, H. (2007) Glucose ingestion fails to inhibit hypothalamic neuronal activity in patients with Typ 2 diabetes. Diabetes, 56, 2547-2550. doi:10.2337/db07-0193
[252] Podingbauer, A. and Ekmekcioglu, C. (2005) Regulation der nahrungsaufnahme: Physiologische mechanismen und klinische relevanz. Journal für Ernahrungsmedizin, 7, 22-29.
[253] Shimizu, H., Inoue, K. and Mori, M. (2007) The leptindependent and -independent melanocortin signaling system: Regulation of feeding and energy expenditure. Journal of Endocrinology, 193, 1-9. doi:10.1677/JOE-06-0144
[254] Fei, H., Okano, H.J., Li, C., Lee, G.H., Zhao, C., Darnell, R. and Friedman. J.M. (1997) Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proceedings of the National Academy of Sciences of the United States of America, 94, 7001-7005.

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