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Pharmacological Modulation of Ghrelin to Induce Weight Loss: Successes and Challenges

  • Obesity (KM Gadde, Section Editor)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Obesity is affecting over 600 million adults worldwide and has numerous negative effects on health. Since ghrelin positively regulates food intake and body weight, targeting its signaling to induce weight loss under conditions of obesity seems promising. Thus, the present work reviews and discusses different possibilities to alter ghrelin signaling.

Recent Findings

Ghrelin signaling can be altered by RNA Spiegelmers, GHSR/Fc, ghrelin-O-acyltransferase inhibitors as well as antagonists, and inverse agonists of the ghrelin receptor. PF-05190457 is the first inverse agonist of the ghrelin receptor tested in humans shown to inhibit growth hormone secretion, gastric emptying, and reduce postprandial glucose levels. Effects on body weight were not examined.

Summary

Although various highly promising agents targeting ghrelin signaling exist, so far, they were mostly only tested in vitro or in animal models. Further research in humans is thus needed to further assess the effects of ghrelin antagonism on body weight especially under conditions of obesity.

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Abbreviations

ACTH:

Adrenocorticotropic hormone

AZ-GHS-22:

Non-CNS penetrant inverse agonist 22

AZ-GHS-38:

CNS penetrant inverse agonist 38

BMI:

Body mass index

CpdB:

Compound B

CpdD:

Compound D

DIO:

Diet-induced obesity

GH:

Growth hormone

GHRP-2:

Growth hormone–releasing peptide-2

GHRP-6:

Growth hormone–releasing peptide 6

GHSR:

Growth hormone secretagogue receptor

GOAT:

Ghrelin-O-acyltransferase

GRLN-R:

Ghrelin receptor

icv:

Intracerebroventricular

POMC:

Proopiomelanocortin

sc:

Subcutaneous

SPM:

RNA Spiegelmer

WHO:

World Health Organization.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. World Health Organization. Obesity and Overweigth. 2018. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight. Accessed 1 June 2019.

  2. Klok MD, Jakobsdottir S, Drent ML. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes Rev. 2007;8(1):21–34. https://doi.org/10.1111/j.1467-789X.2006.00270.x.

    Article  CAS  Google Scholar 

  3. 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(6762):656–60. https://doi.org/10.1038/45230.

    Article  CAS  PubMed  Google Scholar 

  4. Davenport AP, Bonner TI, Foord SM, Harmar AJ, Neubig RR, Pin JP, et al. LVI. Ghrelin receptor nomenclature, distribution, and function. Pharmacol Rev. 2005;57(4):541–6. https://doi.org/10.1124/pr.57.4.1.

    Article  CAS  PubMed  Google Scholar 

  5. Ariyasu H, Takaya K, Tagami T, Ogawa Y, Hosoda K, Akamizu T, et al. 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(10):4753–8. https://doi.org/10.1210/jcem.86.10.7885.

    Article  CAS  PubMed  Google Scholar 

  6. Date Y, Nakazato M, Hashiguchi S, Dezaki K, Mondal MS, Hosoda H, et al. Ghrelin is present in pancreatic alpha-cells of humans and rats and stimulates insulin secretion. Diabetes. 2002;51(1):124–9.

    Article  CAS  Google Scholar 

  7. Gnanapavan S, Kola B, Bustin SA, Morris DG, McGee P, Fairclough P, et al. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab. 2002;87(6):2988. https://doi.org/10.1210/jcem.87.6.8739.

    Article  CAS  PubMed  Google Scholar 

  8. Barreiro ML, Gaytán F, Caminos JE, Pinilla L, Casanueva FF, Aguilar E, et al. Cellular location and hormonal regulation of ghrelin expression in rat testis. Biol Reprod. 2002;67(6):1768–76. https://doi.org/10.1095/biolreprod.102.006965.

    Article  CAS  PubMed  Google Scholar 

  9. Kojima M, Hamamoto A, Sato T. Ghrelin O-acyltransferase (GOAT), a specific enzyme that modifies ghrelin with a medium-chain fatty acid. J Biochem. 2016;160(4):189–94. https://doi.org/10.1093/jb/mvw046.

    Article  CAS  PubMed  Google Scholar 

  10. Gutierrez JA, Solenberg PJ, Perkins DR, Willency JA, Knierman MD, Jin Z, et al. Ghrelin octanoylation mediated by an orphan lipid transferase. Proc Natl Acad Sci U S A. 2008;105(17):6320–5. https://doi.org/10.1073/pnas.0800708105.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell. 2008;132(3):387–96. https://doi.org/10.1016/j.cell.2008.01.017.

    Article  CAS  PubMed  Google Scholar 

  12. Sakata I, Yang J, Lee CE, Osborne-Lawrence S, Rovinsky SA, Elmquist JK, et al. Colocalization of ghrelin O-acyltransferase and ghrelin in gastric mucosal cells. Am J Physiol Endocrinol Metab. 2009;297(1):E134–41. https://doi.org/10.1152/ajpendo.90859.2008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Stengel A, Goebel M, Wang L, Tache Y, Sachs G, Lambrecht NW. Differential distribution of ghrelin-O-acyltransferase (GOAT) immunoreactive cells in the mouse and rat gastric oxyntic mucosa. Biochem Biophys Res Commun. 2010;392(1):67–71. https://doi.org/10.1016/j.bbrc.2009.12.169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Weibert E, Stengel A. The X/A-like cell revisited - spotlight on the peripheral effects of NUCB2/nesfatin-1 and ghrelin. J Physiol Pharmacol. 2017;68(4):497–520.

    CAS  PubMed  Google Scholar 

  15. Guan XM, Yu H, Palyha OC, McKee KK, Feighner SD, Sirinathsinghji DJ, et al. Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res Mol Brain Res. 1997;48(1):23–9.

    Article  CAS  Google Scholar 

  16. Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000;407(6806):908–13. https://doi.org/10.1038/35038090.

    Article  CAS  PubMed  Google Scholar 

  17. Theander-Carrillo C, Wiedmer P, Cettour-Rose P, Nogueiras R, Perez-Tilve D, Pfluger P, et al. Ghrelin action in the brain controls adipocyte metabolism. J Clin Invest. 2006;116(7):1983–93. https://doi.org/10.1172/jci25811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Davies JS, Kotokorpi P, Eccles SR, Barnes SK, Tokarczuk PF, Allen SK, et al. Ghrelin induces abdominal obesity via GHS-R-dependent lipid retention. Mol Endocrinol (Baltimore, Md). 2009;23(6):914–24. https://doi.org/10.1210/me.2008-0432.

    Article  CAS  Google Scholar 

  19. Rodriguez A, Gomez-Ambrosi J, Catalan V, Gil MJ, Becerril S, Sainz N, et al. Acylated and desacyl ghrelin stimulate lipid accumulation in human visceral adipocytes. Int J Obes (2005). 2009;33(5):541–52. https://doi.org/10.1038/ijo.2009.40.

    Article  CAS  Google Scholar 

  20. Briggs DI, Enriori PJ, Lemus MB, Cowley MA, Andrews ZB. Diet-induced obesity causes ghrelin resistance in arcuate NPY/AgRP neurons. Endocrinology. 2010;151(10):4745–55. https://doi.org/10.1210/en.2010-0556.

    Article  CAS  PubMed  Google Scholar 

  21. Naznin F, Toshinai K, Waise TMZ, NamKoong C, Md Moin AS, Sakoda H, et al. Diet-induced obesity causes peripheral and central ghrelin resistance by promoting inflammation. J Endocrinol. 2015;226(1):81–92. https://doi.org/10.1530/JOE-15-0139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. le Roux CW, Patterson M, Vincent RP, Hunt C, Ghatei MA, Bloom SR. Postprandial plasma ghrelin is suppressed proportional to meal calorie content in normal-weight but not obese subjects. J Clin Endocrinol Metab. 2005;90(2):1068–71. https://doi.org/10.1210/jc.2004-1216.

    Article  CAS  PubMed  Google Scholar 

  23. Onnerfalt J, Erlanson-Albertsson C, Montelius C, Thorngren-Jerneck K. Obese children aged 4–6 displayed decreased fasting and postprandial ghrelin levels in response to a test meal. Acta Paediatrica (1992). 2018;107(3):523–8. https://doi.org/10.1111/apa.14165.

    Article  CAS  Google Scholar 

  24. Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab. 2001;86(12):5992. https://doi.org/10.1210/jcem.86.12.8111.

    Article  CAS  PubMed  Google Scholar 

  25. Venkova K, Mann W, Nelson R, Greenwood-Van MB. Efficacy of ipamorelin, a novel ghrelin mimetic, in a rodent model of postoperative ileus. J Pharmacol Exp Ther. 2009;329(3):1110–6. https://doi.org/10.1124/jpet.108.149211.

    Article  CAS  PubMed  Google Scholar 

  26. Hansen BS, Raun K, Nielsen KK, Johansen PB, Hansen TK, Peschke B, et al. Pharmacological characterisation of a new oral GH secretagogue, NN703. Eur J Endocrinol. 1999;141(2):180–9.

    Article  CAS  Google Scholar 

  27. 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(1–2):109–12.

    Article  CAS  Google Scholar 

  28. Laferrere 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(2):611–4. https://doi.org/10.1210/jc.2004-1719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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 Ped Endocrinol Metab. 2003;16(7):981–5.

    Article  CAS  Google Scholar 

  30. Garcia JM, Polvino WJ. Pharmacodynamic hormonal effects of anamorelin, a novel oral ghrelin mimetic and growth hormone secretagogue in healthy volunteers. Growth Hormon IGF Res. 2009;19(3):267–73. https://doi.org/10.1016/j.ghir.2008.12.003.

    Article  CAS  Google Scholar 

  31. 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. Supp Care Cancer. 2013;21(1):129–37. https://doi.org/10.1007/s00520-012-1500-1.

    Article  Google Scholar 

  32. 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(5):594–600. https://doi.org/10.1634/theoncologist.12-5-594.

    Article  CAS  PubMed  Google Scholar 

  33. Zollers B, Rhodes L, Heinen E. Capromorelin oral solution (ENTYCE(R)) increases food consumption and body weight when administered for 4 consecutive days to healthy adult Beagle dogs in a randomized, masked, placebo controlled study. BMC Vet Res. 2017;13(1):10. https://doi.org/10.1186/s12917-016-0925-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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(12):6280–8. https://doi.org/10.1210/en.2008-0804.

    Article  CAS  PubMed  Google Scholar 

  35. Hassouna R, Labarthe A, Zizzari P, Videau C, Culler M, Epelbaum J, et al. Actions of agonists and antagonists of the ghrelin/GHS-R pathway on GH secretion, appetite, and cFos activity. Front Endocrinol. 2013;4:25. https://doi.org/10.3389/fendo.2013.00025.

    Article  CAS  Google Scholar 

  36. Shearman LP, Wang SP, Helmling S, Stribling DS, Mazur P, Ge L, et al. Ghrelin neutralization by a ribonucleic acid-SPM ameliorates obesity in diet-induced obese mice. Endocrinology. 2006;147(3):1517–26. https://doi.org/10.1210/en.2005-0993.

    Article  CAS  PubMed  Google Scholar 

  37. Helmling S, Maasch C, Eulberg D, Buchner K, Schroder W, Lange C, et al. Inhibition of ghrelin action in vitro and in vivo by an RNA-Spiegelmer. Proc Natl Acad Sci U S A. 2004;101(36):13174–9. https://doi.org/10.1073/pnas.0404175101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Becskei C, Bilik KU, Klussmann S, Jarosch F, Lutz TA, Riediger T. The anti-ghrelin Spiegelmer NOX-B11-3 blocks ghrelin- but not fasting-induced neuronal activation in the hypothalamic arcuate nucleus. J Neuroendocrinol. 2008;20(1):85–92. https://doi.org/10.1111/j.1365-2826.2007.01619.x.

    Article  CAS  PubMed  Google Scholar 

  39. Kobelt P, Helmling S, Stengel A, Wlotzka B, Andresen V, Klapp BF, et al. Anti-ghrelin Spiegelmer NOX-B11 inhibits neurostimulatory and orexigenic effects of peripheral ghrelin in rats. Gut. 2006;55(6):788–92. https://doi.org/10.1136/gut.2004.061010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sangiao-Alvarellos S, Helmling S, Vazquez MJ, Klussmann S, Cordido F. Ghrelin neutralization during fasting-refeeding cycle impairs the recuperation of body weight and alters hepatic energy metabolism. Mol Cell Endocrinol. 2011;335(2):177–88. https://doi.org/10.1016/j.mce.2011.01.010.

    Article  CAS  PubMed  Google Scholar 

  41. Teubner BJ, Bartness TJ. Anti-ghrelin Spiegelmer inhibits exogenous ghrelin-induced increases in food intake, hoarding, and neural activation, but not food deprivation-induced increases. Am J Physiol Regul Integr Comp Physiol. 2013;305(4):R323–33. https://doi.org/10.1152/ajpregu.00097.2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gagnon J, Zhu L, Anini Y, Wang Q. Neutralizing circulating ghrelin by expressing a growth hormone secretagogue receptor-based protein protects against high-fat diet-induced obesity in mice. Gene Ther. 2015;22(9):750–7. https://doi.org/10.1038/gt.2015.38.

    Article  CAS  PubMed  Google Scholar 

  43. Zorrilla EP, Iwasaki S, Moss JA, Chang J, Otsuji J, Inoue K, et al. Vaccination against weight gain. Proc Natl Acad Sci U S A. 2006;103(35):13226–31. https://doi.org/10.1073/pnas.0605376103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Vizcarra JA, Kirby JD, Kim SK, Galyean ML. Active immunization against ghrelin decreases weight gain and alters plasma concentrations of growth hormone in growing pigs. Dom Anim Endocrinol. 2007;33(2):176–89. https://doi.org/10.1016/j.domaniend.2006.05.005.

    Article  CAS  Google Scholar 

  45. Andrade S, Pinho F, Ribeiro AM, Carreira M, Casanueva FF, Roy P, et al. Immunization against active ghrelin using virus-like particles for obesity treatment. Curr Pharm Des. 2013;19(36):6551–8. https://doi.org/10.2174/13816128113199990506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Biotechnology C. Phase I/IIa clinical trial with obese individuals shows no effect of CYT009-GhrQb on weight loss. Cytos Biotechnology Press release November 2006;7.

  47. Yang J, Zhao TJ, Goldstein JL, Brown MS. Inhibition of ghrelin O-acyltransferase (GOAT) by octanoylated pentapeptides. Proc Natl Acad Sci U S A. 2008;105(31):10750–5. https://doi.org/10.1073/pnas.0805353105.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Barnett BP, Hwang Y, Taylor MS, Kirchner H, Pfluger PT, Bernard V, et al. Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor. Science. 2010;330(6011):1689–92. https://doi.org/10.1126/science.1196154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Teuffel P, Wang L, Prinz P, Goebel-Stengel M, Scharner S, Kobelt P, et al. Treatment with the ghrelin-O-acyltransferase (GOAT) inhibitor GO-CoA-Tat reduces food intake by reducing meal frequency in rats. J Physiol Pharmacol. 2015;66(4):493–503.

    CAS  PubMed  Google Scholar 

  50. Rucinski M, Ziolkowska A, Szyszka M, Hochol A, Malendowicz LK. Evidence suggesting that ghrelin O-acyl transferase inhibitor acts at the hypothalamus to inhibit hypothalamo-pituitary-adrenocortical axis function in the rat. Peptides. 2012;35(2):149–59. https://doi.org/10.1016/j.peptides.2012.04.007.

    Article  CAS  PubMed  Google Scholar 

  51. • Zhang S, Mao Y, Fan X. Inhibition of ghrelin o-acyltransferase attenuated lipotoxicity by inducing autophagy via AMPK-mTOR pathway. Drug Des Dev Ther. 2018, 873;12:–85. https://doi.org/10.2147/dddt.s158985. A very recent study identifying the molecular changes induced by GO-CoA-Tat administation.

  52. Garner AL, Janda KD. A small molecule antagonist of ghrelin O-acyltransferase (GOAT). Chem Commun. 2011;47(26):7512–4. https://doi.org/10.1039/c1cc11817j.

    Article  CAS  Google Scholar 

  53. Zhao Y, Ma X, Wang Q, Zhou Y, Zhang Y, Wu L, et al. Nesfatin-1 correlates with hypertension in overweight or obese Han Chinese population. Clin Exp Hypertens(1993). 2015;37(1):51–6. https://doi.org/10.3109/10641963.2014.897722.

    Article  CAS  Google Scholar 

  54. McGovern-Gooch KR, Mahajani NS, Garagozzo A, Schramm AJ, Hannah LG, Sieburg MA, et al. Synthetic triterpenoid inhibition of human ghrelin-O-acyltransferase: the involvement of a functionally required cysteine provides mechanistic insight into ghrelin acylation. Biochemistry. 2017;56(7):919–31. https://doi.org/10.1021/acs.biochem.6b01008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yoneyama-Hirozane M, Deguchi K, Hirakawa T, Ishii T, Odani T, Matsui J, et al. Identification and characterization of a new series of ghrelin O-acyl transferase inhibitors. SLAS Discov. 2018;23(2):154–63. https://doi.org/10.1177/2472555217727097.

    Article  CAS  PubMed  Google Scholar 

  56. Howick K, Griffin BT, Cryan JF, Schellekens H. From belly to brain: targeting the ghrelin receptor in appetite and food intake regulation. Int J Mol Sci. 2017;18(2). https://doi.org/10.3390/ijms18020273.

    Article  Google Scholar 

  57. Lin L, Saha PK, Ma X, Henshaw IO, Shao L, Chang BH, et al. Ablation of ghrelin receptor reduces adiposity and improves insulin sensitivity during aging by regulating fat metabolism in white and brown adipose tissues. Aging Cell. 2011;10(6):996–1010. https://doi.org/10.1111/j.1474-9726.2011.00740.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Veeraragavan K, Sethumadhavan K, Bowers CY. Growth hormone-releasing peptide (GHRP) binding to porcine anterior pituitary and hypothalamic membranes. Life Sci. 1992;50(16):1149–55.

    Article  CAS  Google Scholar 

  59. Lawrence CB, Snape AC, Baudoin FM, Luckman SM. Acute central ghrelin and GH secretagogues induce feeding and activate brain appetite centers. Endocrinology. 2002;143(1):155–62. https://doi.org/10.1210/endo.143.1.8561.

    Article  CAS  PubMed  Google Scholar 

  60. Bellone J, Ghizzoni L, Aimaretti G, Volta C, Boghen MF, Bernasconi S, et al. Growth hormone-releasing effect of oral growth hormone-releasing peptide 6 (GHRP-6) administration in children with short stature. Eur J Endocrinol. 1995;133(4):425–9.

    Article  CAS  Google Scholar 

  61. Ramirez VT, van Oeffelen W, Torres-Fuentes C, Chruscicka B, Druelle C, Golubeva AV, et al. Differential functional selectivity and downstream signaling bias of ghrelin receptor antagonists and inverse agonists. FASEB J. 2019;33(1):518–31. https://doi.org/10.1096/fj.201800655R.

    Article  CAS  PubMed  Google Scholar 

  62. Asakawa A, Inui A, Kaga T, Katsuura G, Fujimiya M, Fujino MA, et al. Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. Gut. 2003;52(7):947–52. https://doi.org/10.1136/gut.52.7.947.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Mosa R, Huang L, Li H, Grist M, LeRoith D, Chen C. Long-term treatment with the ghrelin receptor antagonist [d-Lys3]-GHRP-6 does not improve glucose homeostasis in nonobese diabetic MKR mice. Am J Physiol Regul Integr Comp Physiol. 2018;314(1):R71–r83. https://doi.org/10.1152/ajpregu.00157.2017.

    Article  CAS  PubMed  Google Scholar 

  64. Bowers CY, Tannenbau GS, Coy DH, Hocart SJ. Ghrelin/growth hormone releasing peptide/growth hormone secretatogue receptor antagonists and uses thereof. US Patent Application No. 010389 2007. https://patents.google.com/patent/WO2007127457A2/nl.

  65. Demange L, Boeglin D, Moulin A, Mousseaux D, Ryan J, Berge G, et al. Synthesis and pharmacological in vitro and in vivo evaluations of novel triazole derivatives as ligands of the ghrelin receptor. J Med Chem. 2007;50(8):1939–57. https://doi.org/10.1021/jm070024h.

    Article  CAS  PubMed  Google Scholar 

  66. Moulin A, Demange L, Berge G, Gagne D, Ryan J, Mousseaux D, et al. 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(23):5790–806. https://doi.org/10.1021/jm0704550.

    Article  CAS  PubMed  Google Scholar 

  67. Gomez JL, Ryabinin AE. The effects of ghrelin antagonists [D-Lys(3) ]-GHRP-6 or JMV2959 on ethanol, water, and food intake in C57BL/6J mice. Alcohol Clin Exp Res. 2014;38(9):2436–44. https://doi.org/10.1111/acer.12499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Salome N, Haage D, Perrissoud D, Moulin A, Demange L, Egecioglu E, et al. Anorexigenic and electrophysiological actions of novel ghrelin receptor (GHS-R1A) antagonists in rats. Eur J Pharmacol. 2009;612(1–3):167–73. https://doi.org/10.1016/j.ejphar.2009.03.066.

    Article  CAS  PubMed  Google Scholar 

  69. Torsello A, Bresciani E, Tamiazzo L, Bulgarelli I, Caporali S, Moulin A, et al. Novel potent and selective non-peptide ligands of ghrelin receptor: characterization of endocrine and extraendocrine actions. Endocr Abstr. 2008;16:P575.

    Google Scholar 

  70. Halem HA, Taylor JE, Dong JZ, Shen Y, Datta R, Abizaid A, et al. A novel growth hormone secretagogue-1a receptor antagonist that blocks ghrelin-induced growth hormone secretion but induces increased body weight gain. Neuroendocrinology. 2005;81(5):339–49. https://doi.org/10.1159/000088796.

    Article  CAS  PubMed  Google Scholar 

  71. Ueno S, Yoshida S, Mondal A, Nishina K, Koyama M, Sakata I, et al. In vitro selection of a peptide antagonist of growth hormone secretagogue receptor using cDNA display. Proc Nat Sci U S A. 2012;109(28):11121–6. https://doi.org/10.1073/pnas.1203561109.

    Article  CAS  Google Scholar 

  72. Esler WP, Rudolph J, Claus TH, Tang W, Barucci N, Brown SE, et al. Small-molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss. Endocrinology. 2007;148(11):5175–85. https://doi.org/10.1210/en.2007-0239.

    Article  CAS  PubMed  Google Scholar 

  73. Longo KA, Govek EK, Nolan A, McDonagh T, Charoenthongtrakul S, Giuliana DJ, et al. Pharmacologic inhibition of ghrelin receptor signaling is insulin sparing and promotes insulin sensitivity. J Pharmacol Exp Ther. 2011;339(1):115–24. https://doi.org/10.1124/jpet.111.183764.

    Article  CAS  PubMed  Google Scholar 

  74. Rudolph J, Esler WP, O'Connor S, Coish PD, Wickens PL, Brands M, et al. Quinazolinone derivatives as orally available ghrelin receptor antagonists for the treatment of diabetes and obesity. J Med Chem. 2007;50(21):5202–16. https://doi.org/10.1021/jm070071+.

    Article  CAS  PubMed  Google Scholar 

  75. Hoveyda H, Marsault È, Thomas H, Fraser G, Beaubien S, Mathieu A et al. Macrocyclic ghrelin receptor antagonists and inverse agonists and methods of using the same. US Patent Application No. 0105389 2011 www.google.com/patents/US20110105389.

  76. Els S, Beck-Sickinger AG, Chollet C. Ghrelin receptor: high constitutive activity and methods for developing inverse agonists. Methods Enzymol. 2010;485:103–21. https://doi.org/10.1016/b978-0-12-381296-4.00006-3.

    Article  CAS  PubMed  Google Scholar 

  77. Mokrosinski J, Holst B. Modulation of the constitutive activity of the ghrelin receptor by use of pharmacological tools and mutagenesis. Methods Enzymol. 2010;484:53–73. https://doi.org/10.1016/b978-0-12-381298-8.00003-4.

    Article  CAS  PubMed  Google Scholar 

  78. Holst B, Lang M, Brandt E, Bach A, Howard A, Frimurer TM, et al. Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor. Mol Pharmacol. 2006;70(3):936–46. https://doi.org/10.1124/mol.106.024422.

    Article  CAS  PubMed  Google Scholar 

  79. Els S, Schild E, Petersen PS, Kilian TM, Mokrosinski J, Frimurer TM, et al. An aromatic region to induce a switch between agonism and inverse agonism at the ghrelin receptor. J Med Chem. 2012;55(17):7437–49. https://doi.org/10.1021/jm300414b.

    Article  CAS  PubMed  Google Scholar 

  80. Holst B, Mokrosinski J, Lang M, Brandt E, Nygaard R, Frimurer TM, et al. Identification of an efficacy switch region in the ghrelin receptor responsible for interchange between agonism and inverse agonism. J Biol Chem. 2007;282(21):15799–811. https://doi.org/10.1074/jbc.M609796200.

    Article  CAS  Google Scholar 

  81. • Ge X, Yang H, Bednarek MA, Galon-Tilleman H, Chen P, Chen M, et al. LEAP2 is an endogenous antagonist of the ghrelin receptor. Cell Metab. 2018;27(2):461–9.e6. https://doi.org/10.1016/j.cmet.2017.10.016. This recent study reports the effects of an endogenous GHSR antagonist.

    Article  CAS  PubMed  Google Scholar 

  82. M'Kadmi C, Cabral A, Barrile F, Giribaldi J, Cantel S, Damian M, et al. N-terminal liver-expressed antimicrobial peptide 2 (LEAP2) region exhibits inverse agonist activity toward the ghrelin receptor. J Med Chem. 2019;62(2):965–73. https://doi.org/10.1021/acs.jmedchem.8b01644.

    Article  CAS  PubMed  Google Scholar 

  83. Takahashi B, Funami H, Iwaki T, Maruoka H, Shibata M, Koyama M, et al. Orally active ghrelin receptor inverse agonists and their actions on a rat obesity model. Bioorg Med Chem. 2015;23(15):4792–803. https://doi.org/10.1016/j.bmc.2015.05.047.

    Article  CAS  PubMed  Google Scholar 

  84. Takahashi B, Funami H, Iwaki T, Maruoka H, Nagahira A, Koyama M, et al. 2-Aminoalkyl nicotinamide derivatives as pure inverse agonists of the ghrelin receptor. Bioorg Med Chem Lett. 2015;25(13):2707–12. https://doi.org/10.1016/j.bmcl.2015.04.040.

    Article  CAS  PubMed  Google Scholar 

  85. McCoull W, Barton P, Brown AJ, Bowker SS, Cameron J, Clarke DS, et al. Identification, optimization, and pharmacology of acylurea GHS-R1a inverse agonists. J Med Chem. 2014;57(14):6128–40. https://doi.org/10.1021/jm500610n.

    Article  CAS  PubMed  Google Scholar 

  86. Abegg K, Bernasconi L, Hutter M, Whiting L, Pietra C, Giuliano C, et al. Ghrelin receptor inverse agonists as a novel therapeutic approach against obesity-related metabolic disease. Diabetes Obes Metab. 2017;19(12):1740–50. https://doi.org/10.1111/dom.13020.

    Article  CAS  PubMed  Google Scholar 

  87. Bhattacharya SK, Andrews K, Beveridge R, Cameron KO, Chen C, Dunn M, et al. Discovery of PF-5190457, a potent, selective, and orally bioavailable ghrelin receptor inverse agonist clinical candidate. ACS Med Chem Lett. 2014;5(5):474–9. https://doi.org/10.1021/ml400473x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Cameron KO, Bhattacharya SK, Loomis AK. Small molecule ghrelin receptor inverse agonists and antagonists. J Med Chem. 2014;57(21):8671–91. https://doi.org/10.1021/jm5003183.

    Article  CAS  PubMed  Google Scholar 

  89. Kong J, Chuddy J, Stock IA, Loria PM, Straub SV, Vage C, et al. Pharmacological characterization of the first in class clinical candidate PF-05190457: a selective ghrelin receptor competitive antagonist with inverse agonism that increases vagal afferent firing and glucose-dependent insulin secretion ex vivo. Br J Pharmacol. 2016;173(9):1452–64. https://doi.org/10.1111/bph.13439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. •• Denney WS, Sonnenberg GE, Carvajal-Gonzalez S, Tuthill T, Jackson VM. Pharmacokinetics and pharmacodynamics of PF-05190457: The first oral ghrelin receptor inverse agonist to be profiled in healthy subjects. Br J Clin Pharmacol. 2017;83(2):326–38. https://doi.org/10.1111/bcp.13127. This is the first study testing an inverse agonist of the ghrelin receptor in humans showing inhibitory actions on growth hormone secretion, gastric emptying and postprandial glucose levels as well as safety and torability.

    Article  CAS  PubMed  Google Scholar 

  91. Johansson S, Fredholm BB, Hjort C, Morein T, Kull B, Hu PS. Evidence against adenosine analogues being agonists at the growth hormone secretagogue receptor. Biochem Pharmacol. 2005;70(4):598–605. https://doi.org/10.1016/j.bcp.2005.05.023.

    Article  CAS  PubMed  Google Scholar 

  92. Hermansson NO, Morgan DG, Drmota T, Larsson N. Adenosine is not a direct GHSR agonist--artificial cross-talk between GHSR and adenosine receptor pathways. Acta Physiologica (Oxford, England). 2007;190(1):77–86. https://doi.org/10.1111/j.1365-201X.2007.01691.x.

    Article  CAS  Google Scholar 

  93. NIH U. S National Library of Medicine ClinicalTrails.gov. https://clinicaltrials.gov/ct2/results?term=PF-05190457 Accessed 3 August 2019.

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Funding

This work was supported by funding of the German Research Foundation (STE 1765/3-2) and Charité University Funding (UFF 89/441-176, A.S.).

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  1. Charité Center for Internal Medicine and Dermatology, Charité Center for Internal Medicine and Dermatology, Department for Psychosomatic Medicine; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

    Martha A. Schalla & Andreas Stengel

  2. Department of Psychosomatic Medicine and Psychotherapy, Medical University Hospital Tübingen, Tübingen, Germany

    Andreas Stengel

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  1. Martha A. Schalla
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M.S. wrote the first draft of the paper, and A.S. thoroughly reviewed the manuscript; both authors finalized the manuscript.

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Schalla, M.A., Stengel, A. Pharmacological Modulation of Ghrelin to Induce Weight Loss: Successes and Challenges. Curr Diab Rep 19, 102 (2019). https://doi.org/10.1007/s11892-019-1211-9

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