{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T10:00:36Z","timestamp":1783072836490,"version":"3.54.6"},"reference-count":61,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,11,7]],"date-time":"2016-11-07T00:00:00Z","timestamp":1478476800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,11,7]],"date-time":"2016-11-07T00:00:00Z","timestamp":1478476800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Loss of appetite in the medically ill and ageing populations is a major health problem and a significant symptom in cachexia syndromes, which is the loss of muscle and fat mass. Ghrelin is a gut-derived hormone which can stimulate appetite. Herein we describe a novel, simple, non-peptidic, 2-pyridone which acts as a selective agonist for the ghrelin receptor (GHS-R1a). The small 2-pyridone demonstrated clear agonistic activity in both transfected human cells and mouse hypothalamic cells with endogenous GHS-R1a receptor expression. <jats:italic>In vivo<\/jats:italic> tests with the hit compound showed significant increased food intake following peripheral administration, which highlights the potent orexigenic effect of this novel GHS-R1a receptor ligand.<\/jats:p>","DOI":"10.1038\/srep36456","type":"journal-article","created":{"date-parts":[[2016,11,7]],"date-time":"2016-11-07T10:47:48Z","timestamp":1478515668000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["A Novel Non-Peptidic Agonist of the Ghrelin Receptor with Orexigenic Activity In vivo"],"prefix":"10.1038","volume":"6","author":[{"given":"Elena","family":"Pastor-Cavada","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leticia M.","family":"Pardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalia","family":"Kandil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Torres-Fuentes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah L.","family":"Clarke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamdy","family":"Shaban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard P.","family":"McGlacken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harriet","family":"Schellekens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,11,7]]},"reference":[{"key":"BFsrep36456_CR1","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/528182a","volume":"528","author":"C Lok","year":"2015","unstructured":"Lok, C. Cachexia: The last illness. Nature 528, 182\u2013183 (2015).","journal-title":"Nature"},{"key":"BFsrep36456_CR2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s13539-010-0002-6","volume":"1","author":"S von Haehling","year":"2010","unstructured":"von Haehling, S. & Anker, S. D. Cachexia as a major underestimated and unmet medical need: facts and numbers. J. Cachexia Sarcopenia Muscle 1, 1\u20135 (2010).","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"BFsrep36456_CR3","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1093\/ajcn\/83.6.1345","volume":"83","author":"KC Fearan","year":"2006","unstructured":"Fearan, K. C., Voss, A. C. & Hustead, D. S. Definition of cancer cachexia: effect of weight loss, reduced food intake, and systemic inflammation on functional status and prognosis. Am. J. Clin. Nutr. 83, 1345\u20131350 (2006).","journal-title":"Am. J. Clin. Nutr."},{"key":"BFsrep36456_CR4","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1016\/j.peptides.2011.05.014","volume":"32","author":"ZB Andrews","year":"2011","unstructured":"Andrews, Z. B. Central mechanisms involved in the orexigenic actions of ghrelin. Peptides 32, 2248\u20132255 (2011).","journal-title":"Peptides"},{"key":"BFsrep36456_CR5","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1038\/35051587","volume":"409","author":"M Nakazato","year":"2001","unstructured":"Nakazato, M. et al. A role for ghrelin in the central regulation of feeding. Nature 409, 194\u2013198 (2001).","journal-title":"Nature"},{"key":"BFsrep36456_CR6","first-page":"2179","volume":"45","author":"M Amitani","year":"2013","unstructured":"Amitani, M., Asakawa, A., Amitani, H. & Inui, A. Control of food intake and muscle wasting in cachexia. Int. J. Biochem. Cell. Bio. 45, 2179\u20132185 (2013).","journal-title":"Control of food intake and muscle wasting in cachexia. Int. J. Biochem. Cell. Bio."},{"key":"BFsrep36456_CR7","doi-asserted-by":"crossref","first-page":"17","DOI":"10.4251\/wjgo.v7.i4.17","volume":"7","author":"T Aoyagi","year":"2015","unstructured":"Aoyagi, T., Terracina, K. P., Raza, A., Matsubara, H. & Takabe, K. Cancer cachexia, mechanism and treatment. World J. Gastrointest. Oncol. 7, 17\u201329 (2015).","journal-title":"World J. Gastrointest. Oncol."},{"key":"BFsrep36456_CR8","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.ctrv.2015.09.002","volume":"41","author":"A Esposito","year":"2015","unstructured":"Esposito, A. et al. Mechanisms of anorexia\u2013cachexia syndrome and rational for treatment with selective ghrelin receptor agonist. Cancer Treat. Rev. 41, 793\u2013797 (2015).","journal-title":"Cancer Treat. Rev."},{"key":"BFsrep36456_CR9","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.molmet.2015.03.005","volume":"4","author":"TD Muller","year":"2015","unstructured":"Muller, T. D. et al. Ghrelin. Mol. Metab. 4, 437\u2013460 (2015).","journal-title":"Mol. Metab."},{"key":"BFsrep36456_CR10","first-page":"MC13","volume":"8","author":"N Khatib","year":"2014","unstructured":"Khatib, N. et al. Ghrelin: Ghrelin as a Regulatory Peptide in Growth Hormone Secretion. J Clin. Diagn. Res. 8, MC13\u2013MC17 (2014).","journal-title":"J Clin. Diagn. Res."},{"key":"BFsrep36456_CR11","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.pharmthera.2012.06.004","volume":"135","author":"H Schellekens","year":"2012","unstructured":"Schellekens, H., Finger, B. C., Dinan, T. G. & Cryan, J. F. Ghrelin signaling and obesity: at the interface of stress, mood and food reward. Pharmacol. Ther. 135, 316\u2013326 (2012).","journal-title":"Pharmacol. Ther."},{"key":"BFsrep36456_CR12","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.neuropharm.2009.06.024","volume":"58","author":"H Schellekens","year":"2010","unstructured":"Schellekens, H., Dinan, T. G. & Cryan, J. F. Lean mean fat reducing \u201cghrelin\u201d machine: hypothalamic ghrelin and ghrelin receptors as therapeutic targets in obesity. Neuropharmacology 58, 2\u201316 (2010).","journal-title":"Neuropharmacology"},{"key":"BFsrep36456_CR13","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/35038090","volume":"407","author":"M Tschop","year":"2000","unstructured":"Tschop, M., Smiley, D. L. & Heiman, M. L. Ghrelin induces adiposity in rodents. Nature 407, 908\u2013913 (2000).","journal-title":"Nature"},{"key":"BFsrep36456_CR14","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/45230","volume":"402","author":"M Kojima","year":"1999","unstructured":"Kojima, M. et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402, 656\u2013660 (1999).","journal-title":"Nature"},{"key":"BFsrep36456_CR15","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1530\/eje.0.1500447","volume":"150","author":"T Akamizu","year":"2004","unstructured":"Akamizu, T. et al. Pharmacokinetics, safety, and endocrine and appetite effects of ghrelin administration in young healthy subjects. Eur. J. Endocrinol. 150, 447\u2013455 (2004).","journal-title":"Eur. J. Endocrinol."},{"key":"BFsrep36456_CR16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jep.2014.10.063","volume":"159","author":"YH Lo","year":"2015","unstructured":"Lo, Y. H. et al. Emoghrelin, a unique emodin derivative in Heshouwu, stimulates growth hormone secretion via activation of the ghrelin receptor. J. Ethnopharmacol. 159, 1\u20138 (2015).","journal-title":"J. Ethnopharmacol."},{"key":"BFsrep36456_CR17","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.jep.2013.04.039","volume":"148","author":"Y Jang","year":"2013","unstructured":"Jang, Y. et al. Ghrelin receptor is activated by naringin and naringenin, constituents of a prokinetic agent Poncirus fructus. J. Ethnopharmacol. 148, 459\u2013465 (2013).","journal-title":"J. Ethnopharmacol."},{"key":"BFsrep36456_CR18","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1136\/gut.2005.065896","volume":"54","author":"T Kitazawa","year":"2005","unstructured":"Kitazawa, T., de Smet, B., Verbeke, K., Depoortere, I. & Peeters, T. L. Gastric motor effects of peptide and non-peptide ghrelin agonists in mice in vivo and in vitro. Gut 54, 1078\u20131084 (2005).","journal-title":"Gut"},{"key":"BFsrep36456_CR19","doi-asserted-by":"crossref","first-page":"789","DOI":"10.2217\/fon.14.14","volume":"10","author":"DC Currow","year":"2014","unstructured":"Currow, D. C. & Abernethy, A. P. Anamorelin hydrochloride in the treatment of cancer anorexia-cachexia syndrome. Future Oncol. 10, 789\u2013802 (2014).","journal-title":"Future Oncol."},{"key":"BFsrep36456_CR20","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1517\/14656566.2015.1041500","volume":"16","author":"H Zhang","year":"2015","unstructured":"Zhang, H. & Garcia, J. M. Anamorelin hydrochloride for the treatment of cancer-anorexia-cachexia in NSCLC. Expert. Opin. Pharmacother. 16, 1245\u20131253 (2015).","journal-title":"Expert. Opin. Pharmacother."},{"key":"BFsrep36456_CR21","doi-asserted-by":"crossref","first-page":"5239","DOI":"10.1039\/c3ob40859k","volume":"11","author":"A Goel","year":"2013","unstructured":"Goel, A., Taneja, G., Raghovanshi, A., Kant, R. & Maulik, P. R. Diversity-oriented general protocol for the synthesis of privileged oxygen scaffolds: pyrones, coumarins, benzocoumarins and naphthocoumarins. Org. Biomol. Chem. 11, 5239\u20135253 (2013).","journal-title":"Org. Biomol. Chem."},{"key":"BFsrep36456_CR22","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1039\/b911516c","volume":"21","author":"HJ Jessen","year":"2010","unstructured":"Jessen, H. J. & Gademann, K. 4-Hydroxy-2-pyridone alkaloids: Structures and synthetic approaches. Nat. Prod. Rep. 21, 1168\u20131185 (2010).","journal-title":"Nat. Prod. Rep."},{"key":"BFsrep36456_CR23","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1039\/b416651p","volume":"22","author":"GP McGlacken","year":"2005","unstructured":"McGlacken, G. P. & Fairlamb, I. J. S. 2-Pyrone natural products and mimetics: isolation, characterisation and biological activity. Nat. Prod. Rep. 22, 369\u2013385 (2005).","journal-title":"Nat. Prod. Rep."},{"key":"BFsrep36456_CR24","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1007\/978-1-4939-0823-3_6","volume":"25","author":"H Schellekens","year":"2014","unstructured":"Schellekens, H., Dinan, T. G. & Cryan, J. F. The Ghrelin Receptor: A Novel Therapeutic Target for Obesity. Central Functions of the Ghrelin Receptor 25, 89\u2013122 (2014).","journal-title":"Central Functions of the Ghrelin Receptor"},{"key":"BFsrep36456_CR25","unstructured":"Filler, R., Kobayashi, Y. & Yagupolskii, L. M. Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications (Elsevier, 1993)."},{"key":"BFsrep36456_CR26","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1126\/science.1131943","volume":"317","author":"K Muller","year":"2007","unstructured":"Muller, K., Faeh, C. & Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition. Science 317, 1881\u20131886 (2007).","journal-title":"Science"},{"key":"BFsrep36456_CR27","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1039\/B610213C","volume":"37","author":"S Purser","year":"2008","unstructured":"Purser, S., Moore, P. R., Swallow, S. & Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 37, 320\u2013330 (2008).","journal-title":"Chem. Soc. Rev."},{"key":"BFsrep36456_CR28","doi-asserted-by":"crossref","first-page":"4359","DOI":"10.1021\/jm800219f","volume":"51","author":"WK Hagmann","year":"2008","unstructured":"Hagmann, W. K. The many roles for fluorine in medicinal chemistry. J. Med. Chem. 51, 4359\u20134369 (2008).","journal-title":"J. Med. Chem."},{"key":"BFsrep36456_CR29","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1038\/nature10647","volume":"480","author":"DA Nagib","year":"2011","unstructured":"Nagib, D. A. & MacMillan, D. W. C. Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis. Nature 480, 224\u2013228 (2011).","journal-title":"Nature"},{"key":"BFsrep36456_CR30","doi-asserted-by":"crossref","unstructured":"Clarke, S. L. & McGlacken, G. P. Methyl fluorosulfonyldifluoroacetate (MFSDA): An Underutilised Reagent for Trifluoromethylation. Chem. Eur. J, doi: 10.1002\/chem.201602511 (2016).","DOI":"10.1002\/chem.201780661"},{"key":"BFsrep36456_CR31","doi-asserted-by":"crossref","first-page":"2906","DOI":"10.1016\/j.tet.2015.03.061","volume":"71","author":"SL Clarke","year":"2015","unstructured":"Clarke, S. L. & McGlacken, G. P. Access to trifluoromethylated 4-alkoxy-2-pyrones, pyridones and quinolones. Tetrahedron 71, 2906\u20132913 (2015).","journal-title":"Tetrahedron"},{"key":"BFsrep36456_CR32","doi-asserted-by":"crossref","first-page":"2400","DOI":"10.1210\/me.2005-0059","volume":"19","author":"B Holst","year":"2005","unstructured":"Holst, B., Brandt, E., Bach, A., Heding, A. & Schwartz, T. W. Nonpeptide and Peptide Growth Hormone Secretagogues Act Both as Ghrelin Receptor Agonist and as Positive or Negative Allosteric Modulators of Ghrelin Signaling. Mol Endocrinol. 19, 2400\u20132411 (2005).","journal-title":"Mol Endocrinol."},{"key":"BFsrep36456_CR33","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1371\/journal.pone.0103118","volume":"9","author":"C Torres-Fuentes","year":"2014","unstructured":"Torres-Fuentes, C. et al. Devil\u2019s Claw to Suppress Appetite\u2014Ghrelin Receptor Modulation Potential of a Harpagophytum procumbens Root Extract. PLoS ONE 9, 103\u2013118 (2014).","journal-title":"PLoS ONE"},{"key":"BFsrep36456_CR34","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1111\/jphp.12010","volume":"65","author":"H Schellekens","year":"2013","unstructured":"Schellekens, H. et al. Semagacestat, a \u03b3-secretase inhibitor, activates the growth hormone secretagogue (GHS-R1a) receptor. J. Pharm. Pharmacol. 65, 528\u2013538 (2013).","journal-title":"J. Pharm. Pharmacol."},{"key":"BFsrep36456_CR35","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1074\/jbc.M112.382473","volume":"288","author":"H Schellekens","year":"2013","unstructured":"Schellekens, H., van Oeffelen, W. E. P. A., Dinan, T. G. & Cryan, J. F. Promiscuous Dimerization of the Growth Hormone Secretagogue Receptor (GHS-R1a) Attenuates Ghrelin-mediated Signaling. J. Bio. Chem. 288, 181\u2013191 (2013).","journal-title":"J. Bio. Chem."},{"key":"BFsrep36456_CR36","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/B978-0-12-381296-4.00006-3","volume":"485","author":"S Els","year":"2010","unstructured":"Els, S., Beck-Sickinger, A. G. & Chollet, C. Ghrelin receptor: high constitutive activity and methods for developing inverse agonists. Methods Enzymol. 485, 103\u2013121 (2010).","journal-title":"Methods Enzymol"},{"key":"BFsrep36456_CR37","doi-asserted-by":"crossref","first-page":"2201","DOI":"10.1210\/me.2003-0069","volume":"17","author":"B Holst","year":"2003","unstructured":"Holst, B., Cygankiewicz, A., Jensen, T. H., Ankersen, M. & Schwarz, T. W. High constitutive signaling of the ghrelin receptor-identification of a potent inverse agonist. Mol. Endrocrinol. 17, 2201\u20132210 (2003).","journal-title":"Mol. Endrocrinol."},{"key":"BFsrep36456_CR38","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1038\/nrm2803","volume":"10","author":"SL Ritter","year":"2009","unstructured":"Ritter, S. L. & Hall, R. A. Fine-tuning of GPCR activity by receptor-interacting proteins. Nat. Rev. Mol. Cell. Biol. 10, 819\u2013830 (2009).","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"BFsrep36456_CR39","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1111\/j.1476-5381.2011.01552.x","volume":"165","author":"AC Magalhaes","year":"2012","unstructured":"Magalhaes, A. C., Dunn, H. & Ferguson, S. S. G. Regulation of GPCR activity, trafficking and localization by GPCR-interacting proteins. Br. J. Pharmacol. 165, 1717\u20131736 (2012).","journal-title":"Br. J. Pharmacol"},{"key":"BFsrep36456_CR40","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1210\/edrv.18.5.0316","volume":"18","author":"RG Smith","year":"1997","unstructured":"Smith, R. G. et al. Peptidomimetic regulation of growth hormone secretion, Endocr. Rev. 18, 621\u2013645 (1997).","journal-title":"Endocr. Rev."},{"key":"BFsrep36456_CR41","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1021\/cn500318q","volume":"6","author":"H Schellekens","year":"2015","unstructured":"Schellekens, H. et al. Ghrelin\u2019s Orexigenic Effect Is Modulated via a Serotonin 2C Receptor Interaction. ACS Chem. Neurosci. 6, 1186\u20131197 (2015).","journal-title":"ACS Chem. Neurosci."},{"key":"BFsrep36456_CR42","doi-asserted-by":"crossref","first-page":"7120","DOI":"10.1016\/j.tet.2014.04.029","volume":"70","author":"M-T Nolan","year":"2014","unstructured":"Nolan, M.-T. et al. Pd-catalysed intramolecular regioselective arylation of 2-pyrones, pyridones, coumarins and quinolones by C-H bond functionalization. Tetrahedron 70, 7120\u20137127 (2014).","journal-title":"Tetrahedron"},{"key":"BFsrep36456_CR43","doi-asserted-by":"crossref","first-page":"3540","DOI":"10.1002\/ejoc.201500262","volume":"2015","author":"LM Pardo","year":"2015","unstructured":"Pardo, L. M., Prendergast, A. M., Nolan, M.-T., \u00d3 Muimhneach\u00e1in, E. & McGlacken, G. P. Pd\/Pivalic Acid Mediated Direct Arylation of 2-Pyrones and Related Heterocycles. Eur. J. Org. Chem. 2015, 3540\u20133550 (2015).","journal-title":"Eur. J. Org. Chem."},{"key":"BFsrep36456_CR44","doi-asserted-by":"crossref","first-page":"10904","DOI":"10.1021\/acs.joc.5b02027","volume":"80","author":"M-T Nolan","year":"2015","unstructured":"Nolan, M.-T., Pardo, L. M., Prendergast, A. M. & McGlacken, G. P. Intramolecular Direct Arylation of 3-Halo-2-pyrones and 2-Coumarins. J. Org. Chem. 80, 10904\u201310913 (2015).","journal-title":"J. Org. Chem."},{"key":"BFsrep36456_CR45","doi-asserted-by":"crossref","first-page":"2540","DOI":"10.1021\/acs.orglett.6b00751","volume":"18","author":"K Mackey","year":"2016","unstructured":"Mackey, K. et al. Cyclization of 4-Phenoxy-2-coumarins and 2-Pyrones via a Double C\u2212H Activation. Org. Lett. 18, 2540\u20132543 (2016).","journal-title":"Org. Lett."},{"key":"BFsrep36456_CR46","doi-asserted-by":"crossref","first-page":"5926","DOI":"10.1021\/ja0176346","volume":"124","author":"CA Hansen","year":"2002","unstructured":"Hansen, C. A. & Frost, J. W. Deoxygenation of Polyhydroxybenzenes: An Alternative Strategy for the Benzene-Free Synthesis of Aromatic Chemicals. J. Am. Chem. Soc. 124, 5926\u20135927 (2002).","journal-title":"J. Am. Chem. Soc."},{"key":"BFsrep36456_CR47","doi-asserted-by":"crossref","first-page":"3872","DOI":"10.1016\/j.bmcl.2007.05.004","volume":"17","author":"IV Magedov","year":"2007","unstructured":"Magedov, I. V. et al. Antiproliferative and apoptosis inducing properties of pyrano[3,2-c]pyridones accessible by a one-step multicomponent synthesis. Bio. Med. Chem. Lett. 17, 3872\u20133876 (2007).","journal-title":"Bio. Med. Chem. Lett"},{"key":"BFsrep36456_CR48","doi-asserted-by":"crossref","first-page":"5507","DOI":"10.1016\/S0040-4020(01)93615-4","volume":"28","author":"P Beak","year":"1972","unstructured":"Beak, P., Woods, T. S. & Mueller, D. S. Equilibrium studies: Substituent effects on methoxypyridine-1-methylpyridone equilibria. Tetrahedron 28, 5507\u20135524 (1972).","journal-title":"Tetrahedron"},{"key":"BFsrep36456_CR49","first-page":"257","volume":"2","author":"S Castillo","year":"1982","unstructured":"Castillo, S., Ouadahi, H. & H\u00e9rault, V. Bull. Soc. Chim. Fr. 2, 257\u2013261 (1982).","journal-title":"Bull. Soc. Chim. Fr."},{"key":"BFsrep36456_CR50","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1053\/gast.2001.22158","volume":"120","author":"A Asakawa","year":"2001","unstructured":"Asakawa, A. et al. Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology 120, 337\u2013345 (2001)","journal-title":"Gastroenterology"},{"key":"BFsrep36456_CR51","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1007\/s00213-011-2234-3","volume":"216","author":"BC Finger","year":"2011","unstructured":"Finger, B. C., Schellekens, H., Dinan, T. G. & Cryan, J. F. Is there altered sensitivity to ghrelin-receptor ligands in leptin-deficient mice?: importance of satiety state and time of day. Psychopharmacology 216, 421\u2013429 (2011).","journal-title":"Psychopharmacology"},{"key":"BFsrep36456_CR52","first-page":"1","volume":"247","author":"IBS Gomes","year":"2015","unstructured":"Gomes, I. B. S. et al. The protective effects of oral low-dose quercetin on diabetic nephropathy in hypercholesterolemic mice. Front Physiol. 247, 1\u20138 (2015).","journal-title":"Front Physiol."},{"key":"BFsrep36456_CR53","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.1007\/s00520-013-1800-0","volume":"21","author":"R Northrup","year":"2013","unstructured":"Northrup, R. et al. Effect of ghrelin and anamorelin (ONO-7643), a selective ghrelin receptor agonist, on tumor growth in a lung cancer mouse xenograft model. Support Care Cancer. 21, 2409\u20132415 (2013).","journal-title":"Support Care Cancer."},{"key":"BFsrep36456_CR54","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.lfs.2004.09.001","volume":"76","author":"B Becka","year":"2004","unstructured":"Becka, B., Richya, S. & Stricker-Krongradb, A. Feeding response to ghrelin agonist and antagonist in lean and obese Zucker rats. Life Sciences 76, 473\u2013478 (2004).","journal-title":"Life Sciences"},{"key":"BFsrep36456_CR55","doi-asserted-by":"crossref","first-page":"435","DOI":"10.33549\/physiolres.932488","volume":"62","author":"M Holubov\u00e1","year":"2013","unstructured":"Holubov\u00e1, M. et al. Ghrelin agonist JMV 1843 increases food intake, body weight and expression of orexigenic neuropeptides in mice. Physiol Res. 62, 435\u2013444 (2013).","journal-title":"Physiol Res."},{"key":"BFsrep36456_CR56","doi-asserted-by":"crossref","first-page":"5421","DOI":"10.1046\/j.1432-1327.2000.01606.x","volume":"267","author":"J O\u2019Brien","year":"2000","unstructured":"O\u2019Brien, J., Wilson, I., Orton, T. & Pognan, F. Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity. Eur. J. Biochem. 267, 5421\u20135426 (2000).","journal-title":"Eur. J. Biochem."},{"key":"BFsrep36456_CR57","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1210\/en.2003-0974","volume":"145","author":"JP Camina","year":"2004","unstructured":"Camina, J. P. et al. Desensitization and endocytosis mechanisms of ghrelinactivated growth hormone secretagogue receptor 1a. Endocrinology 145, 930\u2013940 (2004).","journal-title":"Endocrinology"},{"key":"BFsrep36456_CR58","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1359\/jbmr.1999.14.7.1182","volume":"14","author":"MG Murphy","year":"1999","unstructured":"Murphy, M. G. et al. Oral Administration of the Growth Hormone Secretagogue MK-677 Increases Markers of Bone Turnover in Healthy and Functionally Impaired Elderly Adults. J. Bone. Miner. Res. 14, 1182\u20131188 (1999).","journal-title":"J. Bone. Miner. Res."},{"key":"BFsrep36456_CR59","doi-asserted-by":"crossref","first-page":"601","DOI":"10.7326\/0003-4819-149-9-200811040-00003","volume":"149","author":"R Nass","year":"2008","unstructured":"Nass, R. et al. Effects of an Oral Ghrelin Mimetic on Body Composition and Clinical Outcomes in Healthy Older Adults: A Randomized Trial. Ann. Int. Med. 149, 601\u2013611 (2008).","journal-title":"Ann. Int. Med."},{"key":"BFsrep36456_CR60","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.mad.2006.10.001","volume":"128","author":"K Toshinai","year":"2007","unstructured":"Toshinai, K. et al. Ghrelin stimulates growth hormone secretion and food intake in aged rats. Mech. Age. Devel. 128, 182\u2013186 (2007).","journal-title":"Mech. Age. Devel."},{"key":"BFsrep36456_CR61","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1210\/jc.2008-0632","volume":"94","author":"HK White","year":"2009","unstructured":"White, H. K. et al. Effects of an Oral Growth Hormone Secretagogue in Older Adults. J. Clin. Endo. Met. 94, 1198\u20131206 (2009).","journal-title":"J. Clin. Endo. Met."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep36456.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep36456","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep36456.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T01:28:25Z","timestamp":1672882105000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep36456"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,7]]},"references-count":61,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,12,21]]}},"alternative-id":["BFsrep36456"],"URL":"https:\/\/doi.org\/10.1038\/srep36456","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,11,7]]},"assertion":[{"value":"13 June 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 October 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 November 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"36456"}}