Horm Metab Res 2016; 48(01): 1-15
DOI: 10.1055/s-0035-1564149
© Georg Thieme Verlag KG Stuttgart · New York

Ghrelin Receptor Ligands Reaching Clinical Trials: From Peptides to Peptidomimetics; from Agonists to Antagonists

M. Vodnik
1   Chair of Pharmaceutical Biology, Faculty of Pharmacy, Ljubljana, Slovenia
B. Štrukelj
1   Chair of Pharmaceutical Biology, Faculty of Pharmacy, Ljubljana, Slovenia
2   Department of Biotechnology, Jozef Stefan Institute, Slovenia
M. Lunder
1   Chair of Pharmaceutical Biology, Faculty of Pharmacy, Ljubljana, Slovenia
› Author Affiliations
Further Information

Publication History

received 12 March 2015

accepted 02 September 2015

Publication Date:
09 November 2015 (online)


In the recent decades, great progress has been made in the development of ghrelin receptor ligands. The discovery of the first in vitro only active peptide growth hormone secretagogue derived from Met-enkephalin was the foundation for later discoveries of the receptor and the endogenous ligand ghrelin. Since then, the scope of peptides, peptidomimetics, and small-molecules targeting the ghrelin receptor, GHS-R1a, has expanded dramatically. Numerous agonists have been tested in animals and several in humans, and a handful have progressed to clinical trials for indications such as growth hormone release, gastric emptying, and cachexia. However, with the exception of the approval of GHRP-2 for diagnostic purposes in Japan, none of the candidates have been successfully introduced into the market. More recently, the attention of researchers has been concentrated on developing antagonists and inverse agonists for pharmacological treatment of the ever-expanding obese and overweight population. In this review, we describe the development of GHS-R1a targeting agonists, antagonists, and inverse agonists. We focus on current and completed clinical trials and the therapeutic potential of currently available ligands.

  • References

  • 1 Hosoda H, Kojima M, Kangawa K. Biological, physiological, and pharmacological aspects of ghrelin. J Pharmacol Sci 2006; 100: 398-410
  • 2 Ariyasu H, Takaya K, Tagami T, Ogawa Y, Hosoda K, Akamizu T, Suda M, Koh T, Natsui K, Toyooka S, Shirakami G, Usui T, Shimatsu A, Doi K, Hosoda H, Kojima M, Kangawa K, Nakao K. Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J Clin Endocrinol Metab 2001; 86: 4753-4758
  • 3 Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC, Anderson J, Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong SS, Chaung LY, Elbrecht A, Dashkevicz M, Heavens R, Rigby M, Sirinathsinghji DJS, Dean DC, Melillo DG, Patchett AA, Nargund R, Griffin PR, DeMartino JA, Gupta SK, Schaeffer JM, Smith RG, VanderPloeg LHT. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 1996; 273: 974-977
  • 4 Gnanapavan S, Kola B, Bustin SA, Morris DG, McGee P, Fairclough P, Bhattacharya S, Carpenter R, Grossman AB, Korbonits M. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab 2002; 87: 2988
  • 5 Diano S, Farr SA, Benoit SC, McNay EC, da Silva I, Horvath B, Gaskin FS, Nonaka N, Jaeger LB, Banks WA, Morley JE, Pinto S, Sherwin RS, Xu L, Yamada KA, Sleeman MW, Tschop MH, Horvath TL. Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci 2006; 9: 381-388
  • 6 Banks WA, Tschöp M, Robinson SM, Heiman ML. Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure. J Pharmacol Exper Therap 2002; 302: 822-827
  • 7 Date Y, Murakami N, Toshinai K, Matsukura S, Niijima A, Matsuo H, Kangawa K, Nakazato M. The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology 2002; 123: 1120-1128
  • 8 Le Roux C, Neary N, Halsey T, Small C, Martinez-Isla A, Ghatei M, Theodorou N, Bloom S. Ghrelin does not stimulate food intake in patients with surgical procedures involving vagotomy. J Clin Endocrinol Metab 2005; 90: 4521-4524
  • 9 Sakata I, Yamazaki M, Inoue K, Hayashi Y, Kangawa K, Sakai T. Growth hormone secretagogue receptor expression in the cells of the stomach-projected afferent nerve in the rat nodose ganglion. Neurosci Lett 2003; 342: 183-186
  • 10 Zhang W, Lin TR, Hu Y, Fan Y, Zhao L, Stuenkel EL, Mulholland MW. Ghrelin stimulates neurogenesis in the dorsal motor nucleus of the vagus. J Physiol 2004; 559: 729-737
  • 11 Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402: 656-660
  • 12 Takaya K, Ariyasu H, Kanamoto N, Iwakura H, Yoshimoto A, Harada M, Mori K, Komatsu Y, Usui T, Shimatsu A, Ogawa Y, Hosoda K, Akamizu T, Kojima M, Kangawa K, Nakao K. Ghrelin strongly stimulates growth hormone release in humans. J Clin Endocrinol Metab 2000; 85: 4908-4911
  • 13 Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Dhillo WS, Ghatei MA, Bloom SR. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 2001; 86: 5992
  • 14 Neary NM, Small CJ, Wren AM, Lee JL, Druce MR, Palmieri C, Frost GS, Ghatei MA, Coombes RC, Bloom SR. Ghrelin increases energy intake in cancer patients with impaired appetite: acute, randomized, placebo-controlled trial. J Clin Endocrinol Metab 2004; 89: 2832-2836
  • 15 Strasser F, Lutz TA, Maeder MT, Thuerlimann B, Bueche D, Tschöp M, Kaufmann K, Holst B, Brändle von Moss R, Demmer R, Cerny T. Safety tolerability and pharmacokinetics of intravenous ghrelin for cancer-related anorexia/cachexia: a randomised, placebo-controlled, double-blind, double-crossover study. Brit J Cancer 2008; 98: 300-308
  • 16 Nagaya N, Itoh T, Murakami S, Oya H, Uematsu M, Miyatake K, Kangawa K. Treatment of cachexia with ghrelin in patients with COPD. Chest 2005; 128: 1187-1193
  • 17 Hotta M, Ohwada R, Akamizu T, Shibasaki T, Takano K, Kangawa K. Ghrelin increases hunger and food intake in patients with restricting-type anorexia nervosa: a pilot study. Endocr J 2009; 56: 1119-1128
  • 18 Broglio F, Gianotti L, Destefanis S, Fassino S, Abbate Daga G, Mondelli V, Lanfranco F, Gottero C, Gauna C, Hofland L, Van der Lely AJ, Ghigo E. The endocrine response to acute ghrelin administration is blunted in patients with anorexia nervosa, a ghrelin hypersecretory state. Clin Endocrinol 2004; 60: 592-599
  • 19 Miljic D, Pekic S, Djurovic M, Doknic M, Milic N, Casanueva FF, Ghatei M, Popovic V. Ghrelin has partial or no effect on appetite, growth hormone, prolactin, and cortisol release in patients with anorexia nervosa. J Clin Endocrinol Metab 2006; 91: 1491-1495
  • 20 Masuda Y, Tanaka T, Inomata N, Ohnuma N, Tanaka S, Itoh Z, Hosoda H, Kojima M, Kangawa K. Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun 2000; 276: 905-908
  • 21 Edholm T, Levin F, Hellstrom PM, Schmidt PT. Ghrelin stimulates motility in the small intestine of rats through intrinsic cholinergic neurons. Regul Peptides 2004; 121: 25-30
  • 22 Tack J, Depoortere I, Bisschops R, Delporte C, Coulie B, Meulemans A, Janssens J, Peeters T. Influence of ghrelin on interdigestive gastrointestinal motility in humans. Gut 2006; 55: 327-333
  • 23 Ceranowicz P, Warzecha Z, Dembinski A, Sendur R, Cieszkowski J, Ceranowicz D, Pawlik WW, Kuwahara A, Kato I, Konturek PC. Treatment with ghrelin accelerates the healing of acetic acid-induced gastric and duodenal ulcers in rats. J Physiol Pharmacol 2009; 60: 87-98
  • 24 Sibilia V, Rindi G, Pagani F, Rapetti D, Locatelli V, Torsello A, Campanini N, Deghenghi R, Netti C. Ghrelin protects against ethanol-induced gastric ulcers in rats: studies on the mechanisms of action. Endocrinology 2003; 144: 353-359
  • 25 Aimaretti G, Baffoni C, Broglio F, Janssen JA, Corneli G, Deghenghi R, van der Lely AJ, Ghigo E, Arvat E. Endocrine responses to ghrelin in adult patients with isolated childhood-onset growth hormone deficiency. Clin Endocrinol (Oxf) 2002; 56: 765-771
  • 26 Bowers CY. GHRP Historical Perspective. In: Smith R, Thorner M. (eds.). Human growth hormone. New York: Humana Press; 2000: 17-43
  • 27 Moulin A, Brunel L, Verdie P, Gavara L, Martinez J, Fehrentz J-A. Ghrelin receptor ligands: design and synthesis of pseudopeptides and peptidomimetics. Curr Chem Biol 2013; 7: 254-270
  • 28 Moulin A, Brunel L, Boeglin D, Demange L, Ryan J, M’Kadmi C, Denoyelle S, Martinez J, Fehrentz JA. The 1,2,4-triazole as a scaffold for the design of ghrelin receptor ligands: development of JMV 2959, a potent antagonist. Amino Acids 2013; 44: 301-314
  • 29 Bowers CY, Momany F, Reynolds GA, Chang D, Hong A, Chang K. Structure-activity-relationships of a synthetic pentapeptide that specifically releases growth-hormone invitro. Endocrinology 1980; 106: 663-667
  • 30 Bowers CY, Momany FA, Reynolds GA, Hong A. On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology 1984; 114: 1537-1545
  • 31 Wu D, Chen C, Zhang J, Katoh K, Clarke I. Effects in vitro of new growth hormone releasing peptide (GHRP-1) on growth hormone secretion from ovine pituitary cells in primary culture. J Neuroendocrinol 1994; 6: 185-190
  • 32 Elias KA, Ingle GS, Burnier JP, Hammonds RG, McDowell RS, Rawson TE, Somers TC, Stanley MS, Cronin MJ. In vitro characterization of four novel classes of growth hormone-releasing peptide. Endocrinology 1995; 136: 5694-5699
  • 33 Hansen BS, Raun K, Nielsen KK, Johansen PB, Hansen TK, Peschke B, Lau J, Andersen PH, Ankersen M. Pharmacological characterisation of a new oral GH secretagogue, NN703. Eur J Endocrinol 1999; 141: 180-189
  • 34 Walker RF, Codd EE, Barone FC, Nelson AH, Goodwin T, Campbell SA. Oral activity of the growth-hormone releasing peptide His-D-Trp-Ala-Trp-D-Phe-Lys-Nh2 in rats, dogs and monkeys. Life Sci 1990; 47: 29-36
  • 35 Nelson AH, Walker RF, Codd EE, Barone FC. Intranasal activity of the growth hormone releasing peptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 in conscious dogs. Life Sci 1991; 48: 2283-2288
  • 36 Deghenghi R, Cananzi MM, Torsello A, Battisti C, Muller EE, Locatelli V. GH-releasing activity of Hexarelin, a new growth hormone releasing peptide, in infant and adult rats. Life Sci 1994; 54: 1321-1328
  • 37 Lawrence CB, Snape AC, Baudoin FM-H, Luckman SM. Acute central ghrelin and GH secretagogues induce feeding and activate brain appetite centers. Endocrinology 2002; 143: 155-162
  • 38 Ilson BE, Jorkasky DK, Curnow RT, Stote RM. Effect of a new synthetic hexapeptide to selectively stimulate growth hormone release in healthy human subjects. J Clin Endocrinol Metab 1989; 69: 212-214
  • 39 Bowers CY, Reynolds GA, Durham D, Barrera CM, Pezzoli SS, Thorner MO. Growth hormone (GH)-releasing peptide stimulates GH release in normal men and acts synergistically with GH-releasing hormone. J Clin Endocrinol Metab 1990; 70: 975-982
  • 40 Hayashi S, Okimura Y, Yagi H, Uchiyama T, Takeshima Y, Shakutsui S, Oohashi S, Bowers CY, Chihara K. Intranasal administration of His-D-Trp-Ala-Trp-D-Phe-LysNH2 (growth hormone releasing peptide) increased plasma growth hormone and insulin-like growth factor-I levels in normal men. Endocrinol Jpn 1991; 38: 15-21
  • 41 Bowers CY. GH releasing peptides–structure and kinetics. J Pediatr Endocrinol 1993; 6: 21-31
  • 42 Ghigo E, Arvat E, Rizzi G, Bellone J, Nicolosi M, Boffano GM, Mucci M, Boghen MF, Camanni F. Arginine enhances the growth hormone-releasing activity of a synthetic hexapeptide (GHRP-6) in elderly but not in young subjects after oral administration. J Endocrinol Invest 1994; 17: 157-162
  • 43 Bellone J, Ghizzoni L, Aimaretti G, Volta C, Boghen MF, Bernasconi S, Ghigo E. Growth hormone-releasing effect of oral growth hormone-releasing peptide 6 (GHRP-6) administration in children with short stature. Eur J Endocrinol 1995; 133: 425-429
  • 44 Deghenghi R. The development of ‘impervious peptides’ as growth hormone secretagogues. Acta Paediatr 1997; 86: 85-87
  • 45 Burnier JP, Clark RG, Elias KA, Mcdowell RS, Rawson TE, Somers TC, Stanley MS. Low molecular weight peptidomimetic growth hormone secretagogues. Eur Patent No. 0792289 2000 www.google.ga/patents/EP0792289B1?cl=en
  • 46 Yang L, Morriello G, Pan Y, Nargund RP, Barakat K, Prendergast K, Cheng K, Chan WW, Smith RG, Patchett AA. Tripeptide growth hormone secretagogues. Bioorg Med Chem Lett 1998; 8: 759-764
  • 47 Chan C-B, Leung P-K, Wise H, Cheng CHK. Signal transduction mechanism of the seabream growth hormone secretagogue receptor. FEBS Lett 2004; 577: 147-153
  • 48 Ueno S, Yoshida S, Mondal A, Nishina K, Koyama M, Sakata I, Miura K, Hayashi Y, Nemoto N, Nishigaki K, Sakai T. In vitro selection of a peptide antagonist of growth hormone secretagogue receptor using cDNA display. Proc Natl Acad Sci USA 2012; 109: 11121-11126
  • 49 Asakawa A, Inui A, Kaga T, Katsuura G, Fujimiya M, Fujino MA, Kasuga M. Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. Gut 2003; 52: 947-952
  • 50 Kitazawa T, De Smet B, Verbeke K, Depoortere I, Peeters TL. Gastric motor effects of peptide and non-peptide ghrelin agonists in mice in vivo and in vitro. Gut 2005; 54: 1078-1084
  • 51 Patel K, Dixit VD, Lee JH, Kim JW, Schaffer EM, Nguyen D, Taub DD. Identification of ghrelin receptor blocker, D-[Lys3] GHRP-6 as a CXCR4 receptor antagonist. Int J Biol Sci 2012; 8: 108-117
  • 52 Schiöth HB, Muceniece R, Wikberg JES. Characterization of the binding of MSH-B, HP-228, GHRP-6 and 153N-6 to the human melanocortin receptor subtypes. Neuropeptides 1997; 31: 565-571
  • 53 Depoortere I, Thijs T, Peeters T. The contractile effect of the ghrelin receptor antagonist, D-Lys3-GHRP-6, in rat fundic strips is mediated through 5-HT receptors. Eur J Pharmacol 2006; 537: 160-165
  • 54 Bowers CY, Tannenbaum GS, Coy DH, Hocart SJ. Ghrelin/growth hormone releasing peptide/growth hormone secretatogue receptor antagonists and uses thereof. US Patent No. 8536120 2013 www.google.com.tr/patents/US8536120
  • 55 Arvat E, di Vito L, Maccagno B, Broglio F, Boghen MF, Deghenghi R, Camanni F, Ghigo E. Effects of GHRP-2 and hexarelin, two synthetic GH-releasing peptides, on GH, prolactin, ACTH and cortisol levels in man. Comparison with the effects of GHRH, TRH and hCRH. Peptides 1997; 18: 885-891
  • 56 Torsello A, Luoni M, Schweiger F, Grilli R, Guidi M, Bresciani E, Deghenghi R, Muller EE, Locatelli V. Novel hexarelin analogs stimulate feeding in the rat through a mechanism not involving growth hormone release. Eur J Pharmacol 1998; 360: 123-129
  • 57 Imbimbo BP, Mant T, Edwards M, Amin D, Dalton N, Boutignon F, Lenaerts V, Wüthrich P, Deghenghi R. Growth hormone-releasing activity of hexarelin in humans. Eur J Clin Pharmacol 1994; 46: 421-425
  • 58 Arvat E, Maccario M, Vito LD, Broglio F, Benso A, Gottero C, Papotti M, Muccioli G, Dieguez C, Casanueva FF, Deghenghi R, Camanni F, Ghigo E. Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone. J Clin Endocrinol Metab 2001; 86: 1169-1174
  • 59 Ghigo E, Arvat E, Ramunni J, Colao A, Gianotti L, Deghenghi R, Lombardi G, Camanni F. Adrenocorticotropin- and cortisol-releasing effect of hexarelin, a synthetic growth hormone-releasing peptide, in normal subjects and patients with cushing’s syndrome. J Clin Endocrinol Metab 1997; 82: 2439-2444
  • 60 Loche S, Colao A, Cappa M, Bellone J, Aimaretti G, Farello G, Faedda A, Lombardi G, Deghenghi R, Ghigo E. The growth hormone response to hexarelin in children: reproducibility and effect of sex steroids. J Clin Endocrinol Metab 1997; 82: 861-864
  • 61 Ghigo E, Arvat E, Gianotti L, Imbimbo BP, Lenaerts V, Deghenghi R, Camanni F. Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal, and oral administration in man. J Clin Endocrinol Metab 1994; 78: 693-698
  • 62 Ghigo E, Arvat E, Gianotti L, Grottoli S, Rizzi G, Ceda G, Boghen M, Deghenghi R, Camanni F. Short-term administration of intranasal or oral Hexarelin, a synthetic hexapeptide, does not desensitize the growth hormone responsiveness in human aging. Eur J Endocrinol 1996; 135: 407-412
  • 63 Guerlavais V, Boeglin D, Mousseaux D, Oiry C, Heitz A, Deghenghi R, Locatelli V, Torsello A, Ghe C, Catapano F, Muccioli G, Galleyrand JC, Fehrentz JA, Martinez J. New active series of growth hormone secretagogues. J Med Chem 2003; 46: 1191-1203
  • 64 Maccario M, Veldhuis J, Broglio F, Vito L, Arvat E, Deghenghi R, Ghigo E. Impact of two or three daily subcutaneous injections of hexarelin, a synthetic growth hormone (GH) secretagogue, on 24-h GH, prolactin, adrenocorticotropin and cortisol secretion in humans. Eur J Endocrinol 2002; 146: 310-318
  • 65 Laron Z, Frenkel J, Deghenghi R, Anin S, Klinger B, Silbergeld A. Intranasal administration of the GHRP hexarelin accelerates growth in short children. Clin Endocrinol (Oxf) 1995; 43: 631-635
  • 66 Broglio F, Guarracino F, Benso A, Gottero C, Prodam F, Granata R, Avogadri E, Muccioli G, Deghenghi R, Ghigo E. Effects of acute hexarelin administration on cardiac performance in patients with coronary artery disease during by-pass surgery. Eur J Pharmacol 2002; 448: 193-200
  • 67 Bisi G, Podio V, Valetto MR, Broglio F, Bertuccio G, Del Rio G, Arvat E, Boghen MF, Deghenghi R, Muccioli G, Ong H, Ghigo E. Acute cardiovascular and hormonal effects of GH and hexarelin, a synthetic GH-releasing peptide, in humans. J Endocrinol Invest 1999; 22: 266-272
  • 68 Bisi G, Podio V, Valetto MR, Broglio F, Bertuccio G, Aimaretti G, Pelosi E, Del Rio G, Muccioli G, Ong H, Boghen MF, Deghenghi R, Ghigo E. Cardiac effects of hexarelin in hypopituitary adults. Eur J Pharmacol 1999; 381: 31-38
  • 69 Cassoni P, Papotti M, Ghe C, Catapano F, Sapino A, Graziani A, Deghenghi R, Reissmann T, Ghigo E, Muccioli G. Identification, characterization, and biological activity of specific receptors for natural (ghrelin) and synthetic growth hormone secretagogues and analogs in human breast carcinomas and cell lines. J Clin Endocrinol Metab 2001; 86: 1738-1745
  • 70 Broglio F, Benso A, Gottero C, Muccioli G, Deghenghi R, Ghigo E, Arvat E. Endocrine activities of alexamorelin (Ala-His-d-2-methyl-Trp-Ala-Trp-d-Phe-Lys-NH2), a synthetic GH secretagogue, in humans. Eur J Endocrinol 2000; 143: 419-425
  • 71 Muccioli G, Papotti M, Locatelli V, Ghigo E, Deghenghi R. Binding of 125I-labeled ghrelin to membranes from human hypothalamus and pituitary gland. J Endocrinol Invest 2001; 24: RC7-RC9
  • 72 Broglio F, Boutignon F, Benso A, Gottero C, Prodam F, Arvat E, Ghe C, Catapano F, Torsello A, Locatelli V, Muccioli G, Boeglin D, Guerlavais V, Fehrentz JA, Martinez J, Ghigo E, Deghenghi R. EP1572: a novel peptido-mimetic GH secretagogue with potent and selective GH-releasing activity in man. J Endocrinol Invest 2002; 25: RC26-RC28
  • 73 Garcia JM, Swerdloff R, Wang C, Kyle M, Kipnes M, Biller BM, Cook D, Yuen KC, Bonert V, Dobs A, Molitch ME, Merriam GR. Macimorelin (AEZS-130)-stimulated growth hormone (GH) test: validation of a novel oral stimulation test for the diagnosis of adult GH deficiency. J Clin Endocrinol Metab 2013; 98: 2422-2429
  • 74 Ali SA, Garcia JM. Randomized clinical trial of the novel oral ghrelin mimetic macimorelin in the treatment of cancer cachexia: study design and preliminary results. Neuroendocr Tumors MON-327-MON-327
  • 75 Demange L, Boeglin D, Moulin A, Mousseaux D, Ryan J, Berge G, Gagne D, Heitz A, Perrissoud D, Locatelli V, Torsello A, Galleyrand JC, Fehrentz JA, Martinez J. Synthesis and pharmacological in vitro and in vivo evaluations of novel triazole derivatives as ligands of the ghrelin receptor. 1. J Med Chem 2007; 50: 1939-1957
  • 76 Moulin A, Demange L, Berge G, Gagne D, Ryan J, Mousseaux D, Heitz A, Perrissoud D, Locatelli V, Torsello A, Galleyrand JC, Fehrentz JA, Martinez J. Toward potent ghrelin receptor ligands based on trisubstituted 1,2,4-triazole structure. 2. Synthesis and pharmacological in vitro and in vivo evaluations. J Med Chem 2007; 50: 5790-5806
  • 77 Moulin A, Demange L, Ryan J, Mousseaux D, Sanchez P, Bergé G, Gagne D, Perrissoud D, Locatelli V, Torsello A, Galleyrand J-C, Fehrentz J-A, Martinez J. New trisubstituted 1,2,4-triazole derivatives as potent ghrelin receptor antagonists. 3. synthesis and pharmacological in vitro and in vivo evaluations. J Med Chem 2008; 51: 689-693
  • 78 Salomé N, Haage D, Perrissoud D, Moulin A, Demange L, Egecioglu E, Fehrentz J-A, Martinez J, Dickson SL. Anorexigenic and electrophysiological actions of novel ghrelin receptor (GHS-R1A) antagonists in rats. Eur J Pharmacol 2009; 612: 167-173
  • 79 Clifford PS, Rodriguez J, Schul D, Hughes S, Kniffin T, Hart N, Eitan S, Wellman PJ, Brunel L, Fehrentz J-A, Martinez J. Attenuation of cocaine induced locomotor sensitization in rats sustaining genetic or pharmacologic antagonism of ghrelin receptors. Addiction Biol 2012; 17: 956-963
  • 80 Jerlhag E, Egecioglu E, Dickson SL, Engel JA. Ghrelin receptor antagonism attenuates cocaine- and amphetamine-induced locomotor stimulation, accumbal dopamine release, and conditioned place preference. Psychopharmacology 2010; 211: 415-422
  • 81 Wellman PJ, Clifford PS, Rodriguez J, Hughes S, Eitan S, Brunel L, Fehrentz JA, Martinez J. Pharmacologic antagonism of ghrelin receptors attenuates development of nicotine induced locomotor sensitization in rats. Regul Pept 2011; 172: 77-80
  • 82 Stevenson JR, Buirkle JM, Buckley LE, Young KA, Albertini KM, Bohidar AE. GHS-R1A antagonism reduces alcohol but not sucrose preference in prairie voles. Physiol Behav 2015; 147: 23-29
  • 83 Bowers CY. Growth hormone-releasing peptide (GHRP). Cell Mol Life Sci 1998; 54: 1316-1329
  • 84 Raun K, Hansen BS, Johansen NL, Thogersen H, Madsen K, Ankersen M, Andersen PH. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol 1998; 139: 552-561
  • 85 Doi N, Hirotani C, Ukai K, Shimada O, Okuno T, Kurasaki S, Kiyofuji T, Ikegami R, Futamata M, Nakagawa T, Ase K, Chihara K. Pharmacological characteristics of KP-102 (GHRP-2), a potent growth hormone-releasing peptide. Arzneimittelforschung 2004; 54: 857-867
  • 86 Pihoker C, Middleton R, Reynolds GA, Bowers CY, Badger TM. Diagnostic studies with intravenous and intranasal growth hormone-releasing peptide-2 in children of short stature. J Clin Endocrinol Metab 1995; 80: 2987-2992
  • 87 Pihoker C, Badger TM, Reynolds GA, Bowers CY. Treatment effects of intranasal growth hormone releasing peptide-2 in children with short stature. J Endocrinol 1997; 155: 79-86
  • 88 Pihoker C, Kearns GL, French D, Bowers CY. Pharmacokinetics and pharmacodynamics of growth hormone-releasing peptide-2: a phase i study in children. J Clin Endocrinol Metab 1998; 83: 1168-1172
  • 89 Laferrère B, Abraham C, Russell CD, Bowers CY. Growth hormone releasing peptide-2 (ghrp-2), like ghrelin, increases food intake in healthy men. J Clin Endocrinol Metab 2005; 90: 611-614
  • 90 Mericq V, Cassorla F, Bowers CY, Avila A, Gonen B, Merriam GR. Changes in appetite and body weight in response to long-term oral administration of the ghrelin agonist GHRP-2 in growth hormone deficient children. J Pediatr Endocrinol Metab 2003; 16: 981-985
  • 91 Nasu R, Kumagai Y, Kogetsu H, Tsujimoto M, Ohtani H, Sawada Y. Physiologically based pharmacokinetic model for pralmorelin hydrochloride in rats. Drug Metab Dispos 2005; 33: 1488-1494
  • 92 Pralmorelin: GHRP 2, GPA 748, growth hormone-releasing peptide 2, KP-102 D, KP-102 LN, KP-102D, KP-102LN. Drugs R D 2004; 5: 236-239
  • 93 Johansen PB, Nowak J, Skjaerbaek C, Flyvbjerg A, Andreassen TT, Wilken M, Orskov H. Ipamorelin, a new growth-hormone-releasing peptide, induces longitudinal bone growth in rats. Growth Horm IGF Res 1999; 9: 106-113
  • 94 Polvino WJ, Nelson R, Mann WR. Method of stimulating the motility of the gastrointestinal system using ipamorelin. US Patent No. 8039456 2011 www.google.com.ar/patents/US8039456
  • 95 Johansen PB, Hansen KT, Andersen JV, Johansen NL. Pharmacokinetic evaluation of ipamorelin and other peptidyl growth hormone secretagogues with emphasis on nasal absorption. Xenobiotica 1998; 28: 1083-1092
  • 96 Beck DE, Sweeney WB, McCarter MD. Prospective, randomized, controlled, proof-of-concept study of the Ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients. Int J Colorectal Dis 2014; 29: 1527-1534
  • 97 Ankersen M, Johansen NL, Madsen K, Hansen BS, Raun K, Nielsen KK, Thogersen H, Hansen TK, Peschke B, Lau J, Lundt BF, Andersen PH. A new series of highly potent growth hormone-releasing peptides derived from ipamorelin. J Med Chem 1998; 41: 3699-3704
  • 98 Hansen TK, Ankersen M, Hansen BS, Raun K, Nielsen KK, Lau J, Peschke B, Lundt BF, Thogersen H, Johansen NL, Madsen K, Andersen PH. Novel orally active growth hormone secretagogues. J Med Chem 1998; 41: 3705-3714
  • 99 Zdravkovic M, Sogaard B, Ynddal L, Christiansen T, Agerso H, Thomsen MS, Falch JE, Ilondo MM. The pharmacokinetics, pharmacodynamics, safety and tolerability of a single dose of NN703, a novel orally active growth hormone secretagogue in healthy male volunteers. Growth Horm IGF Res 2000; 10: 193-198
  • 100 Zdravkovic M, Christiansen T, Eliot L, Agersoe H, Thomsen MS, Falch JF, Sogaard B, Ynddal L, Ilondo MM. The pharmacokinetics, pharmacodynamics, safety and tolerability following 7 days daily oral treatment with NN703 in healthy male subjects. Growth Horm IGF Res 2001; 11: 41-48
  • 101 Zdravkovic M, Olsen AK, Christiansen T, Schulz R, Taub ME, Thomsen MS, Rasmussen MH, Ilondo MM. A clinical study investigating the pharmacokinetic interaction between NN703 (tabimorelin), a potential inhibitor of CYP3A4 activity, and midazolam, a CYP3A4 substrate. Eur J Clin Pharmacol 2003; 58: 683-688
  • 102 Hansen TK, Ankersen M, Raun K, Hansen BS. Highly potent growth hormone secretagogues: hybrids of NN703 and ipamorelin. Bioorg Med Chem Lett 2001; 11: 1915-1918
  • 103 Ankersen M, Nielsen KK, Hansen TK, Raun K, Hansen BS. Growth hormone secretagogues derived from NN703 with hydrazides as c-terminal. Eur J Med Chem 2000; 35: 487-497
  • 104 Garcia JM, Polvino WJ. Pharmacodynamic hormonal effects of anamorelin, a novel oral ghrelin mimetic and growth hormone secretagogue in healthy volunteers. Growth Horm IGF Res 2009; 19: 267-273
  • 105 Garcia JM, Polvino WJ. Effect on body weight and safety of RC-1291, a novel, orally available ghrelin mimetic and growth hormone secretagogue: results of a phase I, randomized, placebo-controlled, multiple-dose study in healthy volunteers. Oncologist 2007; 12: 594-600
  • 106 Garcia J, Boccia RV, Graham C, Kumor K, Polvino W. A phase II randomized, placebo-controlled, double-blind study of the efficacy and safety of RC-1291 (RC) for the treatment of cancer cachexia. J Clin Oncol 2007; 25 (18 Suppl) 9133
  • 107 Garcia JM, Friend J, Allen S. Therapeutic potential of anamorelin, a novel, oral ghrelin mimetic, in patients with cancer-related cachexia: a multicenter, randomized, double-blind, crossover, pilot study. Support Care Cancer 2013; 21: 129-137
  • 108 Garcia JM, Boccia RV, Graham CD, Yan Y, Duus EM, Allen S, Friend J. Anamorelin for patients with cancer cachexia: an integrated analysis of two phase 2, randomised, placebo-controlled, double-blind trials. Lancet Oncol 2015; 16: 108-116
  • 109 Northrup R, Kuroda K, Duus EM, Barnes SR, Cheatham L, Wiley T, Pietra C. 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 2013; 21: 2409-2415
  • 110 Temel JS, Currow DC, Fearon K, Yan Y, Friend J, Abernethy AP. Phase III trials of anamorelin in patients with advanced non-small cell lung cancer (NSCLC) and cachexia (ROMANA 1 and 2). J Clin Oncol (Meeting Abstracts) 2015; 33: 9500
  • 111 Bednarek MA, Feighner SD, Pong SS, McKee KK, Hreniuk DL, Silva MV, Warren VA, Howard AD, Van Der Ploeg LH, Heck JV. Structure-function studies on the new growth hormone-releasing peptide, ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a. J Med Chem 2000; 43: 4370-4376
  • 112 Matsumoto M, Hosoda H, Kitajima Y, Morozumi N, Minamitake Y, Tanaka S, Matsuo H, Kojima M, Hayashi Y, Kangawa K. Structure–activity relationship of ghrelin: pharmacological study of ghrelin peptides. Biochem Biophys Res Commun 2001; 287: 142-146
  • 113 Torsello A, Ghe’ C, Bresciani E, Catapano F, Ghigo E, Deghenghi R, Locatelli V, Muccioli G. Short ghrelin peptides neither displace ghrelin binding in vitro nor stimulate gh release in vivo. Endocrinology 2002; 143: 1968-1968
  • 114 Van Craenenbroeck M, Gregoire F, De Neef P, Robberecht P, Perret J. Ala-scan of ghrelin (1–14): interaction with the recombinant human ghrelin receptor. Peptides 2004; 25: 959-965
  • 115 Kangawa K, Kojima M, Hosoda H, Matsuo H, Minamitake Y. Novel peptides. European Patent No. 1197496 2007 www.google.com/patents/EP1197496A1?cl=en
  • 116 Rubinfeld H, Hadani M, Taylor JE, Dong JZ, Comstock J, Shen Y, DeOliveira D, Datta R, Culler MD, Shimon I. Novel ghrelin analogs with improved affinity for the GH secretagogue receptor stimulate GH and prolactin release from human pituitary cells. Eur J Endocrinol 2004; 151: 787-795
  • 117 Strassburg S, Anker SD, Castaneda TR, Burget L, Perez-Tilve D, Pfluger PT, Nogueiras R, Halem H, Dong JZ, Culler MD, Datta R, Tschöp MH. Long-term effects of ghrelin and ghrelin receptor agonists on energy balance in rats. American J Physiol Endocrinol Metab 2008; 295: E78-E84
  • 118 Tabarin A, Diz-Chaves Y, Consoli D, Monsaingeon M, Bale TL, Culler MD, Datta R, Drago F, Vale WW, Koob GF, Zorrilla EP, Contarino A. Role of the corticotropin-releasing factor receptor type 2 in the control of food intake in mice: a meal pattern analysis. Eur J Neurosci 2007; 26: 2303-2314
  • 119 Halem HA, Taylor JE, Dong JZ, Shen Y, Datta R, Abizaid A, Diano S, Horvath T, Zizzari P, Bluet-Pajot MT, Epelbaum J, Culler MD. Novel analogs of ghrelin: physiological and clinical implications. Eur J Endocrinol 2004; 151 (Suppl. 01) S71-S75
  • 120 Fischer K, Finan B, Clemmensen C, van der Ploeg LHT, Tschöp MH, Müller TD. The pentapeptide RM-131 promotes food intake and adiposity in wildtype mice but not in mice lacking the ghrelin receptor. Front Nutr 2014; 1: 31
  • 121 Nagaya N, Moriya J, Yasumura Y, Uematsu M, Ono F, Shimizu W, Ueno K, Kitakaze M, Miyatake K, Kangawa K. Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure. Circulation 2004; 110: 3674-3679
  • 122 Palus S, von Haehling S, Doehner W, Datta R, Zhang J, Dong JZ, Culler MD, Anker SD, Springer J. Effect of application route of the ghrelin analog BIM-28131 (RM-131) on body weight and body composition in a rat heart failure model. Int J Cardiol 2013; 168: 2369-2374
  • 123 Palus S, Schur R, Akashi YJ, Bockmeyer B, Datta R, Halem H, Dong J, Culler MD, Adams V, Anker SD, Springer J. Ghrelin and its analogues, BIM-28131 and BIM-28125, Improve body weight and regulate the expression of MuRF-1 and MAFbx in a rat heart failure model. PLoS One 2011; 6: e26865
  • 124 Van der Ploeg L, Laken H, Sharma S, Datta R, Halem H, Dong J, Touvay C, Teillot M, Noonan P, Tartaglia L, Stoner L, Henderson B, Gottesdiener K, Culler M. Preclinical gastrointestinal prokinetic efficacy and endocrine effects of the ghrelin mimetic RM-131. Life Sci 2014; 109: 20-29
  • 125 Shin A, Camilleri M, Busciglio I, Burton D, Stoner E, Noonan P, Gottesdiener K, Smith SA, Vella A, Zinsmeister AR. Randomized controlled phase Ib study of ghrelin agonist, RM-131, in type 2 diabetic women with delayed gastric emptying: pharmacokinetics and pharmacodynamics. Diabetes Care 2013; 36: 41-48
  • 126 Shin A, Camilleri M, Busciglio I, Burton D, Smith SA, Vella A, Ryks M, Rhoten D, Zinsmeister AR. The ghrelin agonist RM-131 accelerates gastric emptying of solids and reduces symptoms in patients with type 1 diabetes mellitus. Clin Gastroenterol Hepatol 2013; 11: 1453-1459 e1454
  • 127 Lenk K, Palus S, Schur R, Datta R, Dong J, Culler MD, Anker S, Springer J, Schuler G, Adams V. Effect of ghrelin and its analogues, BIM-28131 and BIM-28125, on the expression of myostatin in a rat heart failure model. J Cachexia Sarcopenia Muscle 2013; 4: 63-69
  • 128 Zizzari P, Halem H, Taylor J, Dong JZ, Datta R, Culler MD, Epelbaum J, Bluet-Pajot MT. Endogenous ghrelin regulates episodic growth hormone (GH) secretion by amplifying GH Pulse amplitude: evidence from antagonism of the GH secretagogue-R1a receptor. Endocrinology 2005; 146: 3836-3842
  • 129 Hassouna R, Labarthe A, Zizzari P, Videau C, Culler M, Epelbaum J, Tolle V. Actions of agonists and antagonists of the ghrelin/GHS-R pathway on GH secretion, appetite, and cFos activity. Front Endocrinol (Lausanne) 2013; 4: 25
  • 130 Halem HA, Taylor JE, Dong JZ, Shen Y, Datta R, Abizaid A, Diano S, Horvath TL, Culler MD. A novel growth hormone secretagogue-1a receptor antagonist that blocks ghrelin-induced growth hormone secretion but induces increased body weight gain. Neuroendocrinology 2005; 81: 339-349
  • 131 Palucki BL, Feighner SD, Pong S-S, McKee KK, Hreniuk DL, Tan C, Howard AD, Van der Ploeg LHY, Patchett AA, Nargund RP. Spiro (indoline-3,4′-piperidine) growth hormone secretagogues as ghrelin mimetics. Bioorg Med Chem Lett 2001; 11: 1955-1957
  • 132 Deghenghi R. Ghrelin antagonists. US Patent Application No. 0187938 2002 www.google.com/patents/US20020187938
  • 133 Denef C. Paracrinicity: the story of 30 years of cellular pituitary crosstalk. J Neuroendocrinol 2008; 20: 1-70
  • 134 Cheng K, Wei L, Chaung L-Y, WW-S Chan, Butler B, Smith RG. Inhibition of L-692,429-stimulated rat growth hormone release by a weak substance P antagonist: L-756,867. J Endocrinol 1997; 152: 155-158
  • 135 Holst B, Cygankiewicz A, Jensen TH, Ankersen M, Schwartz TW. High constitutive signaling of the ghrelin receptor–identification of a potent inverse agonist. Mol Endocrinol 2003; 17: 2201-2210
  • 136 Holst B, Lang M, Brandt E, Bach A, Howard A, Frimurer TM, Beck-Sickinger A, Schwartz TW. Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor. Mol Pharmacol 2006; 70: 936-946
  • 137 Els S, Schild E, Petersen PS, Kilian T-M, Mokrosinski J, Frimurer TM, Chollet C, Schwartz TW, Holst B, Beck-Sickinger AG. An aromatic region to induce a switch between agonism and inverse agonism at the ghrelin receptor. J Med Chem 2012; 55: 7437-7449
  • 138 Sivertsen B, Lang M, Frimurer TM, Holliday ND, Bach A, Els S, Engelstoft MS, Petersen PS, Madsen AN, Schwartz TW, Beck-Sickinger AG, Holst B. Unique interaction pattern for a functionally biased ghrelin receptor agonist. J Biol Chem 2011; 286: 20845-20860
  • 139 Fraser GL, Hoveyda HR, Tannenbaum GS. Pharmacological demarcation of the growth hormone, gut motility and feeding effects of ghrelin using a novel ghrelin receptor agonist. Endocrinology 2008; 149: 6280-6288
  • 140 Hoveyda HR, Marsault E, Gagnon R, Mathieu AP, Vezina M, Landry A, Wang Z, Benakli K, Beaubien S, Saint-Louis C, Brassard M, Pinault JF, Ouellet L, Bhat S, Ramaseshan M, Peng X, Foucher L, Beauchemin S, Bherer P, Veber DF, Peterson ML, Fraser GL. Optimization of the potency and pharmacokinetic properties of a macrocyclic ghrelin receptor agonist (Part I): Development of ulimorelin (TZP-101) from hit to clinic. J Med Chem 2011; 54: 8305-8320
  • 141 Venkova K, Fraser G, Hoveyda HR, Greenwood-Van Meerveld B. Prokinetic effects of a new ghrelin receptor agonist TZP-101 in a rat model of postoperative ileus. Dig Dis Sci 2007; 52: 2241-2248
  • 142 Fraser GL, Venkova K, Hoveyda HR, Thomas H, Greenwood-Van Meerveld B. Effect of the ghrelin receptor agonist TZP-101 on colonic transit in a rat model of postoperative ileus. Eur J Pharmacol 2009; 604: 132-137
  • 143 Lasseter KC, Shaughnessy L, Cummings D, Pezzullo JC, Wargin W, Gagnon R, Oliva J, Kosutic G. Ghrelin agonist (TZP-101): safety, pharmacokinetics and pharmacodynamic evaluation in healthy volunteers: a phase I, first-in-human study. J Clin Pharmacol 2008; 48: 193-202
  • 144 Ejskjaer N, Vestergaard ET, Hellstrom PM, Gormsen LC, Madsbad S, Madsen JL, Jensen TA, Pezzullo JC, Christiansen JS, Shaughnessy L, Kosutic G. Ghrelin receptor agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis. Aliment Pharmacol Ther 2009; 29: 1179-1187
  • 145 Ejskjaer N, Dimcevski G, Wo J, Hellstrom PM, Gormsen LC, Sarosiek I, Softeland E, Nowak T, Pezzullo JC, Shaughnessy L, Kosutic G, McCallum R. Safety and efficacy of ghrelin agonist TZP-101 in relieving symptoms in patients with diabetic gastroparesis: a randomized, placebo-controlled study. Neurogastroenterol Motil 2010; 22: e1069-e1281
  • 146 Bochicchio G, Charlton P, Pezzullo JC, Kosutic G, Senagore A. Ghrelin agonist TZP-101/Ulimorelin accelerates gastrointestinal recovery independently of opioid use and surgery type: covariate analysis of phase 2 data. World J Surg 2012; 36: 39-45
  • 147 Popescu I, Fleshner PR, Pezzullo JC, Charlton PA, Kosutic G, Senagore AJ. The ghrelin agonist TZP-101 for management of postoperative ileus after partial colectomy: a randomized, dose-ranging, placebo-controlled clinical trial. Dis Colon Rectum 2010; 53: 126-134
  • 148 Wo JM, Ejskjaer N, Hellstrom PM, Malik RA, Pezzullo JC, Shaughnessy L, Charlton P, Kosutic G, McCallum RW. Randomised clinical trial: ghrelin agonist TZP-101 relieves gastroparesis associated with severe nausea and vomiting–randomised clinical study subset data. Aliment Pharmacol Ther 2011; 33: 679-688
  • 149 Shaw M, Pediconi C, McVey D, Mondou E, Quinn J, Chamblin B, Rousseau F. Safety and efficacy of ulimorelin administered postoperatively to accelerate recovery of gastrointestinal motility following partial bowel resection: results of two randomized, placebo-controlled phase 3 trials. Dis Colon Rectum 2013; 56: 888-897
  • 150 Ejskjaer N, Wo JM, Esfandyari T, Mazen Jamal M, Dimcevski G, Tarnow L, Malik RA, Hellstrom PM, Mondou E, Quinn J, Rousseau F, McCallum RW. A phase 2a, randomized, double-blind 28-day study of TZP-102 a ghrelin receptor agonist for diabetic gastroparesis. Neurogastroenterol Motil 2013; 25: e140-e150
  • 151 McCallum RW, Lembo A, Esfandyari T, Bhandari BR, Ejskjaer N, Cosentino C, Helton N, Mondou E, Quinn J, Rousseau F. Phase 2b, randomized, double-blind 12-week studies of TZP-102, a ghrelin receptor agonist for diabetic gastroparesis. Neurogastroenterol Motil 2013; 25: e705-e717
  • 152 Fraser GL, Hoveyda HR, Peterson ML. Methods of using macrocyclic modulators of the ghrelin receptor. US Patent Application No. 0288163 2011 www.google.co.ug/patents/US20110288163
  • 153 Fraser GL, Hoveyda HR, Peterson ML. Methods of using macrocyclic agonists of the ghrelin receptor for treatment of gastrointestinal motility disorders. US Patent No. 8088733 2012 www.google.com.ar/patents/US8088733
  • 154 Hoveyda H, Marsault É, Thomas H, Fraser G, Beaubien S, Mathieu A, Beignet J, Bonin MA, Phoenix S, Drutz D. Macrocyclic ghrelin receptor antagonists and inverse agonists and methods of using the same. US Patent Application No. 0105389 2011 www.google.com/patents/US20110105389
  • 155 Schoen WR, Pisano JM, Prendergast K, Wyvratt Jr MJ, Fisher MH, Cheng K, Chan WW, Butler B, Smith RG, Ball RG. A novel 3-substituted benzazepinone growth hormone secretagogue (L-692,429). J Med Chem 1994; 37: 897-906
  • 156 Hickey G, Jacks T, Judith F, Taylor J, Schoen WR, Krupa D, Cunningham P, Clark J, Smith RG. Efficacy and specificity of L-692,429, a novel nonpeptidyl growth hormone secretagogue, in beagles. Endocrinology 1994; 134: 695-701
  • 157 Gertz BJ, Barrett JS, Eisenhandler R, Krupa DA, Wittreich JM, Seibold JR, Schneider SH. Growth hormone response in man to L-692,429, a novel nonpeptide mimic of growth hormone-releasing peptide-6. J Clin Endocrinol Metab 1993; 77: 1393-1397
  • 158 Aloi JA, Gertz BJ, Hartman ML, Huhn WC, Pezzoli SS, Wittreich JM, Krupa DA, Thorner MO. Neuroendocrine responses to a novel growth hormone secretagogue, L-692,429, in healthy older subjects. J Clin Endocrinol Metab 1994; 79: 943-949
  • 159 Chapman IM, Hartman ML, Pezzoli SS, Thorner MO. Enhancement of pulsatile growth hormone secretion by continuous infusion of a growth hormone-releasing peptide mimetic, L-692,429, in older adults–a clinical research center study. J Clin Endocrinol Metab 1996; 81: 2874-2880
  • 160 Patchett AA, Nargund RP, Tata JR, Chen MH, Barakat KJ, Johnston DB, Cheng K, Chan WW, Butler B, Hickey G, Jacks T, Schleim K, Pong S-S, Chaung L-YP, Chen HY, Frazier E, Leung KH, Chiu S-HL, Smith RG. Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue. Proc Natl Acad Sci USA 1995; 92: 7001-7005
  • 161 Jacks T, Smith R, Judith F, Schleim K, Frazier E, Chen H, Krupa D, Hora D, Nargund J, Patchett R, Hickey AG. MK-0677, a potent, novel, orally active growth hormone (GH) secretagogue: GH, insulin-like growth factor I, and other hormonal responses in beagles. Endocrinology 1996; 137: 5284-5289
  • 162 Smith RG, Pong SS, Hickey G, Jacks T, Cheng K, Leonard R, Cohen CJ, Arena JP, Chang CH, Drisko J, Wyvratt M, Fisher M, Nargund R, Patchett A. Modulation of pulsatile GH release through a novel receptor in hypothalamus and pituitary gland. Recent Prog Horm Res 1996; 51: 261-285 discussion 285–266
  • 163 Adunsky A, Chandler J, Heyden N, Lutkiewicz J, Scott BB, Berd Y, Liu N, Papanicolaou DA. MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fracture: A multicenter, randomized, placebo-controlled phase IIb study. Arch Gerontol Geriat 2011; 53: 183-189
  • 164 Yang L, Morriello G, Patchett AA, Leung K, Jacks T, Cheng K, Schleim KD, Feeney W, Chan WW, Chiu SH, Smith RG. 1-[2R-(2-amino-2-methylpropionylamino)-3-(1H-indol-3-yl)propionyl]-3-benzylpiperidine-3S-carboxylic acid ethyl ester (L-163,540): a potent, orally bioavailable, and short-duration growth hormone secretagogue. J Med Chem 1998; 41: 2439-2441
  • 165 Carpino PA, Lefker BA, Toler SM, Pan LC, Hadcock JR, Cook ER, DiBrino JN, Campeta AM, DeNinno SL, Chidsey-Frink KL, Hada WA, Inthavongsay J, Mangano FM, Mullins MA, Nickerson DF, Ng O, Pirie CM, Ragan JA, Rose CR, Tess DA, Wright AS, Yu L, Zawistoski MP, DaSilva-Jardine PA, Wilson TC, Thompson DD. Pyrazolinone-piperidine dipeptide growth hormone secretagogues (GHSs). Discovery of capromorelin. Bioorg Med Chem 2003; 11: 581-590
  • 166 Pan L, Carpino P, Lefker B, Ragan J, Toler S, Pettersen J, Nettleton D, Ng O, Pirie C, Chidsey-Frink K, Lu B, Nickerson D, Tess D, Mullins M, MacLean D, DaSilva-Jardine P, Thompson D. Preclinical pharmacology of CP-424,391, and orally active pyrazolinone-piperidine growth hormone secretagogue. Endocrine 2001; 14: 121-132
  • 167 Ellis AG, Zeglinski PT, Brown DJ, Frauman AG, Millard M, Furness JB. Pharmacokinetics of the ghrelin agonist capromorelin in a single ascending dose Phase-I safety trial in spinal cord-injured and able-bodied volunteers. Spinal Cord 2015; 53: 103-108
  • 168 Carpino PA, Lefker BA, Toler SM, Pan LC, Hadcock JR, Murray MC, Cook ER, DiBrino JN, DeNinno SL, Chidsey-Frink KL, Hada WA, Inthavongsay J, Lewis SK, Mangano FM, Mullins MA, Nickerson DF, Ng O, Pirie CM, Ragan JA, Rose CR, Tess DA, Wright AS, Yu L, Zawistoski MP, Pettersen JC, DaSilva-Jardine PA, Wilson TC, Thompson DD. Discovery and biological characterization of capromorelin analogues with extended half-lives. Bioorg Med Chem Lett 2002; 12: 3279-3282
  • 169 Lugar CW, Clay MP, Lindstrom TD, Woodson AL, Smiley D, Heiman ML, Dodge JA. Synthesis and biological evaluation of an orally active ghrelin agonist that stimulates food consumption and adiposity in rats. Bioorg Med Chem Lett 2004; 14: 5873-5876
  • 170 Seyler DE, Dodge JA, Osborne JJ, Cox KL, Viswanath D, Wilmot AF, Keaton MJ, Heiman ML, Bryant HU, Cutler GB. Effect of growth hormone secretagogue LY444711 on IGF-1, growth hormone, and cortisol levels in beagle dog after one and seven daily oral doses. Drug Develop Res 2000; 49: 260-265
  • 171 Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML. Circulating ghrelin levels are decreased in human obesity. Diabetes 2001; 50: 707-709
  • 172 Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, Nozoe S, Hosoda H, Kangawa K, Matsukura S. Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab 2002; 87: 240-244
  • 173 Roh SG, Matsunaga N, Hidaka S, Hidari H. Characteristics of growth hormone secretion responsiveness to growth hormone-releasing peptide-2 (GHRP-2 or KP102) in calves. Endocr J 1996; 43: 291-298
  • 174 Nakagawa T, Ukai K, Ohyama T, Koida M, Okamura H. Effects of the synthesized growth hormone releasing peptide, KP-102, on growth hormone release in sodium glutamate monohydrate-treated low growth rats. Life Sci 1996; 59: 705-712
  • 175 Shepherd B, Eckert S, Parhar I, Vijayan M, Wakabayashi I, Hirano T, Grau E, Chen T. The hexapeptide KP-102 (d-ala-d-beta-Nal-ala-trp-d-phe-lys-NH2) stimulates growth hormone release in a cichlid fish (Ooreochromis mossambicus). J Endocrinol 2000; 167: R7-R10
  • 176 Kuriyama H, Hotta M, Wakabayashi I, Shibasaki T. A 6-day intracerebroventricular infusion of the growth hormone-releasing peptide KP-102 stimulates food intake in both non-stressed and intermittently-stressed rats. Neurosci Lett 2000; 282: 109-112
  • 177 Hashizume T, Sasaki K, Kobayashi S, Nitta Y. Intrahypothalamic perfusion of KP102 stimulates growth hormone release in goats. Endocr J 1998; 45: 53-59
  • 178 Hashizume T, Kawai M, Ohtsuki K, Ishii A, Numata M. Oral administration of peptidergic growth hormone (GH) secretagogue KP102 stimulates GH release in goats. Domest Anim Endocrinol 1999; 16: 31-39
  • 179 Nijland EA, Strasburger CJ, Popp-Snijders C, van der Wal PS, van der Veen EA. A five day treatment with daily subcutaneous injections of growth hormone-releasing peptide-2 causes response attenuation and does not stimulate insulin-like growth factor-I secretion in healthy young men. Eur J Endocrinol 1998; 139: 395-401
  • 180 Pietra C, Takeda Y, Tazawa-Ogata N, Minami M, Yuanfeng X, Duus EM, Northrup R. Anamorelin HCl (ONO-7643), a novel ghrelin receptor agonist, for the treatment of cancer anorexia-cachexia syndrome: preclinical profile. J Cachexia Sarcopenia Muscle 2014; 5: 329-337
  • 181 Bailey AR, Smith RG, Leng G. The nonpeptide growth hormone secretagogue, MK-0677, activates hypothalamic arcuate nucleus neurons in vivo. J Neuroendocrinol 1998; 10: 111-118
  • 182 Kirk SE, Gertz BJ, Schneider SH, Hartman ML, Pezzoli SS, Wittreich JM, Krupa DA, Seibold JR, Thorner MO. Effect of obesity and feeding on the growth hormone (GH) response to the GH secretagogue L-692,429 in young men. J Clin Endocrinol Metab 1997; 82: 1154-1159
  • 183 Prahalada S, Block G, Handt L, DeBurlet G, Cahill M, Hoe CM, van Zwieten MJ. Insulin-like growth factor-1 and growth hormone (GH) levels in canine cerebrospinal fluid are unaffected by GH or GH secretagogue (MK-0677) administration. Horm Metab Res 1999; 31: 133-137
  • 184 Schleim K-D, Jacks T, Cunningham P, Feeney W, Frazier EG, Niebauer GW, Zhang D, Chen H, Smith RG, Hickey G. Increases in circulating insulin-like growth factor 1 levels by the oral growth hormone secretagogue MK-0677 in the beagle are dependent upon pituitary mediation. Endocrinology 1999; 140: 1552-1558
  • 185 Svensson J, Lonn L, Jansson JO, Murphy G, Wyss D, Krupa D, Cerchio K, Polvino W, Gertz B, Boseaus I, Sjostrom L, Bengtsson BA. Two-month treatment of obese subjects with the oral growth hormone (GH) secretagogue MK-677 increases GH secretion, fat-free mass, and energy expenditure. J Clin Endocrinol Metab 1998; 83: 362-369
  • 186 Khojasteh-Bakht SC, O’Donnell JP, Fouda HG, Potchoiba MJ. Metabolism, pharmacokinetics, tissue distribution, and excretion of [14C]CP-424391 in rats. Drug Metab Dispos 2005; 33: 190-199
  • 187 Dhurandhar EJ, Allison DB, van Groen T, Kadish I. Hunger in the absence of caloric restriction improves cognition and attenuates alzheimer’s disease pathology in a mouse model. PLoS One 2013; 8: e60437