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Endocrine Reviews 18 (5): 621-645
Copyright © 1997 by The Endocrine Society

Peptidomimetic Regulation of Growth Hormone Secretion

Roy G. Smith, Lex H. T. Van der Ploeg, Andrew D. Howard, Scott D. Feighner, Kang Cheng, Gerard J. Hickey, Matthew J. Wyvratt, Jr., Mike H. Fisher, Ravi P. Nargund and Arthur A. Patchett

Merck Research Laboratories, Rahway, New Jersey 07065

I. Introduction
II. Identification of Peptidomimetic GH Secretagogues
A. Mechanism of action of GHRH, GHRP-6, and somatostatin
B. In vitro assays
III. Molecular Design by Medicinal Chemistry
A. Benzolactams and L-692,429
B. Spiroindanes and MK-0677
C. Isonipecotic acid peptidomimetics
IV. Characterization of the MK-0677 Receptor
A. Pituitary gland
B. Hypothalamus
V. Signal Transduction Pathway
VI. Cloning the GH Secretagogue Receptor
A. Chromosomal localization
VII. Action of the Peptidomimetic GH Secretagogues in the Central Nervous System
VIII. Peptidomimetic GH Secretagogues in Vivo
A. Animal models
B. Clinical studies in humans
IX. Regulation of Pulsatile GH Release
A. GHRH and somatostatin
B. The role of GHS-R
X. Concluding Comments




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K. Wallenius, K. Sjogren, X.-D. Peng, S. Park, V. Wallenius, J.-L. Liu, M. Umaerus, H. Wennbo, O. Isaksson, L. Frohman, et al.
Liver-Derived IGF-I Regulates GH Secretion at the Pituitary Level in Mice
Endocrinology, November 1, 2001; 142(11): 4762 - 4770.
[Abstract] [Full Text] [PDF]

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 DiabetesHome page
J. Kamegai, H. Tamura, T. Shimizu, S. Ishii, H. Sugihara, and I. Wakabayashi
Chronic Central Infusion of Ghrelin Increases Hypothalamic Neuropeptide Y and Agouti-Related Protein mRNA Levels and Body Weight in Rats
Diabetes, November 1, 2001; 50(11): 2438 - 2443.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
M. Papotti, P. Cassoni, M. Volante, R. Deghenghi, G. Muccioli, and E. Ghigo
Ghrelin-Producing Endocrine Tumors of the Stomach and Intestine
J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 5052 - 5059.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
T. L. Horvath, S. Diano, P. Sotonyi, M. Heiman, and M. Tschop
Minireview: Ghrelin and the Regulation of Energy Balance--A Hypothalamic Perspective
Endocrinology, October 1, 2001; 142(10): 4163 - 4169.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
A. Garcia, C. V. Alvarez, R. G. Smith, and C. Dieguez
Regulation of PIT-1 Expression By Ghrelin and GHRP-6 Through the GH Secretagogue Receptor
Mol. Endocrinol., September 1, 2001; 15(9): 1484 - 1495.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
J. L. Clasey, A. Weltman, J. Patrie, J. Y. Weltman, S. Pezzoli, C. Bouchard, M. O. Thorner, and M. L. Hartman
Abdominal Visceral Fat and Fasting Insulin Are Important Predictors of 24-Hour GH Release Independent of Age, Gender, and Other Physiological Factors
J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3845 - 3852.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
M. J. Bray, T. M. Vick, N. Shah, S. M. Anderson, L. W. Rice, A. Iranmanesh, W. S. Evans, and J. D. Veldhuis
Short-Term Estradiol Replacement in Postmenopausal Women Selectively Mutes Somatostatin's Dose-Dependent Inhibition of Fasting Growth Hormone Secretion
J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3143 - 3149.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
L. S. Farhy, M. Straume, M. L. Johnson, B. Kovatchev, and J. D. Veldhuis
A construct of interactive feedback control of the GH axis in the male
Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2001; 281(1): R38 - R51.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
U. Pagotto, G. Marsicano, F. Fezza, M. Theodoropoulou, Y. Grubler, J. Stalla, T. Arzberger, A. Milone, M. Losa, V. Di Marzo, et al.
Normal Human Pituitary Gland and Pituitary Adenomas Express Cannabinoid Receptor Type 1 and Synthesize Endogenous Cannabinoids: First Evidence for a Direct Role of Cannabinoids on Hormone Modulation at the Human Pituitary Level
J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2687 - 2696.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
N. Nagaya, M. Kojima, M. Uematsu, M. Yamagishi, H. Hosoda, H. Oya, Y. Hayashi, and K. Kangawa
Hemodynamic and hormonal effects of human ghrelin in healthy volunteers
Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2001; 280(5): R1483 - R1487.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
P. Cassoni, M. Papotti, C. Ghè, F. Catapano, A. Sapino, A. Graziani, R. Deghenghi, T. Reissmann, E. Ghigo, and G. Muccioli
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., April 1, 2001; 86(4): 1738 - 1745.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
E. Arvat, M. Maccario, L. Di Vito, F. Broglio, A. Benso, C. Gottero, M. Papotti, G. Muccioli, C. Dieguez, F. F. Casanueva, et al.
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., March 1, 2001; 86(3): 1169 - 1174.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
M. Korbonits, S. A. Bustin, M. Kojima, S. Jordan, E. F. Adams, D. G. Lowe, K. Kangawa, and A. B. Grossman
The Expression of the Growth Hormone Secretagogue Receptor Ligand Ghrelin in Normal and Abnormal Human Pituitary and Other Neuroendocrine Tumors
J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 881 - 887.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
R. Salvatori, X. Fan, J. A. Phillips III, R. Espigares-Martin, I. Martin de Lara, K. L. Freeman, L. Plotnick, A. Al-Ashwal, and M. A. Levine
Three New Mutations in the Gene for the Growth Hormone (GH)-Releasing Hormone Receptor in Familial Isolated GH Deficiency Type IB
J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 273 - 279.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
L. Gianotti, M. Maccario, F. Lanfranco, J. Ramunni, L. Di Vito, S. Grottoli, E. E. Muller, E. Ghigo, and E. Arvat
Arginine Counteracts the Inhibitory Effect of Recombinant Human Insulin-Like Growth Factor I on the Somatotroph Responsiveness to Growth Hormone-Releasing Hormone in Humans
J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3604 - 3608.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
M. Papotti, C. Ghè, P. Cassoni, F. Catapano, R. Deghenghi, E. Ghigo, and G. Muccioli
Growth Hormone Secretagogue Binding Sites in Peripheral Human Tissues
J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3803 - 3807.
[Abstract] [Full Text]

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 EndocrinologyHome page
R. Nass, J. Gilrain, S. Anderson, B. Gaylinn, A. Dalkin, R. Day, M. Peruggia, and M. O. Thorner
High Plasma Growth Hormone (GH) Levels Inhibit Expression of GH Secretagogue Receptor Messenger Ribonucleic Acid Levels in the Rat Pituitary
Endocrinology, June 1, 2000; 141(6): 2084 - 2089.
[Abstract] [Full Text] [PDF]

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 Drug Metab. Dispos.Home page
M. Roumi, S. Marleau, P. du Souich, T. Maggi, R. Deghenghi, and H. Ong
Kinetics and Disposition of Hexarelin, A Peptidic Growth Hormone Secretagogue, in Rats
Drug Metab. Dispos., January 1, 2000; 28(1): 44 - 50.
[Abstract] [Full Text]

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 Mol. Endocrinol.Home page
O. C. Palyha, S. D. Feighner, C. P. Tan, K. K. McKee, D. L. Hreniuk, Y.-D. Gao, K. D. Schleim, L. Yang, G. J. Morriello, R. Nargund, et al.
Ligand Activation Domain of Human Orphan Growth Hormone (GH) Secretagogue Receptor (GHS-R) Conserved from Pufferfish to Humans
Mol. Endocrinol., January 1, 2000; 14(1): 160 - 169.
[Abstract] [Full Text]

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 Circ. Res.Home page
V. Bodart, J. F. Bouchard, N. McNicoll, E. Escher, P. Carriere, E. Ghigo, T. Sejlitz, M. G. Sirois, D. Lamontagne, and H. Ong
Identification and Characterization of a New Growth Hormone-Releasing Peptide Receptor in the Heart
Circ. Res., October 29, 1999; 85(9): 796 - 802.
[Abstract] [Full Text] [PDF]

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 ScienceHome page
S. D. Feighner, C. P. Tan, K. K. McKee, O. C. Palyha, D. L. Hreniuk, S. Pong, C. P. Austin, D. Figueroa, D. MacNeil, M. A. Cascieri, et al.
Receptor for Motilin Identified in the Human Gastrointestinal System
Science, June 25, 1999; 284(5423): 2184 - 2188.
[Abstract] [Full Text]

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 EndocrinologyHome page
J. L. Ramírez, J. P. Castaño, R. Torronteras, A. J. Martínez-Fuentes, L. S. Frawley, S. García-Navarro, and F. Gracia-Navarro
Growth Hormone (GH)-Releasing Factor Differentially Activates Cyclic Adenosine 3',5'-Monophosphate- and Inositol Phosphate-Dependent Pathways to Stimulate GH Release in Two Porcine Somatotrope Subpopulations
Endocrinology, April 1, 1999; 140(4): 1752 - 1759.
[Abstract] [Full Text]

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 Physiol. Rev.Home page
E. E. Muller, V. Locatelli, and D. Cocchi
Neuroendocrine Control of Growth Hormone Secretion
Physiol Rev, April 1, 1999; 79(2): 511 - 607.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
J. Mendlewicz, P. Linkowski, M. Kerkhofs, R. Leproult, G. Copinschi, and E. Van Cauter
Genetic Control of 24-Hour Growth Hormone Secretion in Man: A Twin Study
J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 856 - 862.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
H. G. Maheshwari, A. Rahim, S. M. Shalet, and G. Baumann
Selective Lack of Growth Hormone (GH) Response to the GH-Releasing Peptide Hexarelin in Patients with GH-Releasing Hormone Receptor Deficiency
J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 956 - 959.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
E. Ghigo, L. Gianotti, E. Arvat, J. Ramunni, M. R. Valetto, F. Broglio, M. Rolla, F. Cavagnini, and E. E. Müller
Effects of Recombinant Human Insulin-Like Growth Factor I Administration on Growth Hormone (GH) Secretion, Both Spontaneous and Stimulated by GH-Releasing Hormone or Hexarelin, a Peptidyl GH Secretagogue, in Humans
J. Clin. Endocrinol. Metab., January 1, 1999; 84(1): 285 - 290.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
E. Arvat, R. Giordano, J. Ramunni, G. Arnaldi, A. Colao, R. Deghenghi, G. Lombardi, F. Mantero, F. Camanni, and E. Ghigo
Adrenocorticotropin and Cortisol Hyperresponsiveness to Hexarelin in Patients with Cushing's Disease Bearing a Pituitary Microadenoma, But Not in Those with Macroadenoma
J. Clin. Endocrinol. Metab., December 1, 1998; 83(12): 4207 - 4211.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
M. M. Skinner, R. Nass, B. Lopes, E. R. Laws, and M. O. Thorner
Growth Hormone Secretagogue Receptor Expression in Human Pituitary Tumors
J. Clin. Endocrinol. Metab., December 1, 1998; 83(12): 4314 - 4320.
[Abstract] [Full Text]

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 Am. J. Physiol. Endocrinol. Metab.Home page
C. Wagner, S. R. Caplan, and G. S. Tannenbaum
Genesis of the ultradian rhythm of GH secretion: a new model unifying experimental observations in rats
Am J Physiol Endocrinol Metab, December 1, 1998; 275(6): E1046 - E1054.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
M. Maghnie, V. Spica-Russotto, M. Cappa, M. Autelli, C. Tinelli, P. Civolani, R. Deghenghi, F. Severi, and S. Loche
The Growth Hormone Response to Hexarelin in Patients with Different Hypothalamic-Pituitary Abnormalities
J. Clin. Endocrinol. Metab., November 1, 1998; 83(11): 3886 - 3889.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
K. Hanew, A. Utsumi, A. Tanaka, H. Ikeda, and Y. Yokogoshi
Secretory Mechanisms of Growth Hormone (GH)-Releasing Peptide-, GH-Releasing Hormone-, and Thyrotropin-Releasing Hormone-Induced GH Release in Patients with Acromegaly
J. Clin. Endocrinol. Metab., October 1, 1998; 83(10): 3578 - 3583.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
M. Korbonits, R. A. Jacobs, S. J. B. Aylwin, J. M. Burrin, P. L. M. Dahia, J. P. Monson, J. Honegger, R. Fahlbush, P. J. Trainer, S. L. Chew, et al.
Expression of the Growth Hormone Secretagogue Receptor in Pituitary Adenomas and Other Neuroendocrine Tumors
J. Clin. Endocrinol. Metab., October 1, 1998; 83(10): 3624 - 3630.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
S. Nielsen, S. Mellemkjær, L. M. Rasmussen, T. Ledet, J. Astrup, J. Weeke, and J. O. L. Jørgensen
Gene Transcription of Receptors for Growth Hormone-Releasing Peptide and Somatostatin in Human Pituitary Adenomas
J. Clin. Endocrinol. Metab., August 1, 1998; 83(8): 2997 - 3000.
[Abstract] [Full Text]

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 EndocrinologyHome page
D. F. Carmignac, P. A. Bennett, and I. C. A. F. Robinson
Effects of Growth Hormone Secretagogues on Prolactin Release in Anesthetized Dwarf (dw/dw) Rats
Endocrinology, August 1, 1998; 139(8): 3590 - 3596.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
D. Micic, V. Popovic, M. Doknic, D. Macut, C. Dieguez, and F. F. Casanueva
Preserved Growth Hormone (GH) Secretion in Aged and Very Old Subjects after Testing with the Combined Stimulus GH-Releasing Hormone plus GH-Releasing Hexapeptide-6
J. Clin. Endocrinol. Metab., July 1, 1998; 83(7): 2569 - 2572.
[Abstract] [Full Text]

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 Physiol. Rev.Home page
T. D. ETHERTON and D. E. BAUMAN
Biology of Somatotropin in Growth and Lactation of Domestic Animals
Physiol Rev, July 1, 1998; 78(3): 745 - 761.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
H. Hosoda, M. Kojima, H. Matsuo, and K. Kangawa
Purification and Characterization of Rat des-Gln14-Ghrelin, a Second Endogenous Ligand for the Growth Hormone Secretagogue Receptor
J. Biol. Chem., July 14, 2000; 275(29): 21995 - 22000.
[Abstract] [Full Text] [PDF]

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 Circ. Res.Home page
V. Bodart, M. Febbraio, A. Demers, N. McNicoll, P. Pohankova, A. Perreault, T. Sejlitz, E. Escher, R.L. Silverstein, D. Lamontagne, et al.
CD36 Mediates the Cardiovascular Action of Growth Hormone-Releasing Peptides in the Heart
Circ. Res., May 3, 2002; 90(8): 844 - 849.
[Abstract] [Full Text] [PDF]


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