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Examorelin

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Examorelin

Examorelin
Systematic (IUPAC) name
(2S)-6-amino-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]amino]-3-(2-methyl-1H-indol-3-yl)propanoyl]amino]propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-phenylpropanoyl]amino]hexanamide
Clinical data
Routes of
administration
Intravenous, subcutaneous, intranasal, oral[1]
Pharmacokinetic data
Biological half-life ~55 minutes[2]
Identifiers
CAS Registry Number
ATC code None
PubChem CID:
IUPHAR/BPS
ChemSpider
Synonyms L-Histidyl-2-methyl-D-tryptophyl-L-alanyl-L-tryptophyl-D-phenylalanyl-L-lysinamide
Chemical data
Formula C47H58N12O6
Molecular mass 887.04022 g/mol

Examorelin (synthetic, peptidic, orally-active, centrally-penetrant, and highly selective agonist of the ghrelin/growth hormone secretagogue receptor (GHSR) and a growth hormone secretagogue which was developed by Mediolanum Farmaceutici.[3][4][5][6][7] It is a hexapeptide with the amino acid sequence His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2 which was derived from GHRP-6 (which, in turn, is an analogue of ghrelin).[5][6]

Examorelin substantially and dose-dependently increases plasma levels of growth hormone (GH) in animals and humans.[2] In addition, similarly to pralmorelin (GHRP-2) and GHRP-6, it slightly and dose-dependently stimulates the release of prolactin, adrenocorticotropic hormone (ACTH), and cortisol in humans.[2][8] There are conflicting reports on the ability of examorelin to elevate insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 1 (IGFBP-1) levels in humans, with some studies finding no increase and others finding a slight yet statistically significant increase.[2][9][10][11] Examorelin does not affect plasma levels of glucose, luteinizing hormone (LH), follicle-stimulating hormone (FSH), or thyroid-stimulating hormone (TSH) in humans.[2]

Examorelin releases more GH than does growth hormone-releasing hormone (GHRH) in humans,[8][12] and produces synergistic effects on GH release in combination with GHRH, resulting in "massive" increases in plasma GH levels even with only low doses of examorelin.[13][14][15] Pre-administration of GH blunts the GH-releasing effect of examorelin, while, in contrast, fully abolishing the effect of GHRH.[14][16] Pre-treatment with IGF-1 also blunts the GH-elevating effect of examorelin.[17] Testosterone, testosterone enanthate, and ethinyl estradiol, though not oxandrolone, have been found to significantly potentiate the GH-releasing effects of examorelin in humans.[18][19] In accordance, likely due to increases in sex steroid levels, puberty has also been found to significantly augment the GH-elevating actions of examorelin in humans.[20]

A partial and reversible tolerance to the GH-releasing effects of examorelin occurs in humans with long-term administration (50–75% decrease in efficacy over the course of weeks to months).[21][22]

Examorelin reached phase II clinical trials for the treatment of growth hormone deficiency and congestive heart failure but did not complete development and was never marketed.[6][23][24]

See also

References

  1. ^ Ghigo E, Arvat E, Gianotti L, Imbimbo BP, Lenaerts V, Deghenghi R, et al. (1994). "Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal, and oral administration in man.". J Clin Endocrinol Metab 78 (3): 693–8.  
  2. ^ a b c d e Imbimbo, B.P.; Mant, T.; Edwards, M.; Amin, D.; Dalton, N.; Boutignon, F.; Lenaerts, V.; Wďż˝thrich, P.; Deghenghi, R. (1994). "Growth hormone-releasing activity of hexarelin in humans". Eur J Clin Pharmacol (Springer Science $\mathplus$ Business Media) 46 (5).  
  3. ^ C.R. Ganellin; David J. Triggle (21 November 1996). Dictionary of Pharmacological Agents. CRC Press. pp. 617–.  
  4. ^ I.K. Morton; Judith M. Hall (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 117–.  
  5. ^ a b Moulin A, Ryan J, Martinez J, Fehrentz JA (2007). "Recent developments in ghrelin receptor ligands.". ChemMedChem 2 (9): 1242–59.  
  6. ^ a b c Wang Y, Tomlinson B (2009). "Tesamorelin, a human growth hormone releasing factor analogue.". Expert Opin Investig Drugs 18 (3): 303–10.  
  7. ^ Carpino, Philip A (2002). "Recent developments in ghrelin receptor (GHS)". Expert Opin. Ther. Patents (Informa Healthcare) 12 (11): 1599–1618.  
  8. ^ a b Arvat, Emanuela; Vito, Lidia Di; Maccagno, Barbara; Broglio, Fabio; Boghen, Muni F; Deghenghi, Romano; Camanni, Franco; Ghigo, Ezio (1997). "Effects of GHRP". Peptides (Elsevier BV) 18 (6): 885–891.  
  9. ^ Ghigo, E; Arvat, E; Gianotti, L; Grottoli, S; Rizzi, G; Ceda, G.; Boghen, M.; Deghenghi, R; Camanni, F (1996). "Short-term administration of intranasal or oral Hexarelin, a synthetic hexapeptide, does not desensitize the growth hormone responsiveness in human aging". European Journal of Endocrinology (BioScientifica) 135 (4): 407–412.  
  10. ^ Laron, Z.; Frenkel, J.; Deghenghl, R.; Anin, S.; Klinger, B.; Siibergeld, A. (1995). "Intranasal administration of the GHRP". Clinical Endocrinology (Wiley-Blackwell) 43 (5): 631–635.  
  11. ^ Frenkel, J.; Silbergeld, A.; Deghenghi, R.; Laron, Z. (1995). "Short Term Effect of Intranasal Administration of Hexarelin". Journal of Pediatric Endocrinology and Metabolism (Walter de Gruyter (GmbH)) 8 (1).  
  12. ^ Maccario, M.; Arvat, E.; Procopio, M.; Gianotti, L.; Grottoli, S.; Imbimbo, B.P.; Lenaerts, V.; Deghenghi, R.; Camanni, F.; Ghigo, E. (1995). "Metabolic modulation of the growth hormone-releasing activity of hexarelin in man". Metabolism (Elsevier BV) 44 (1): 134–138.  
  13. ^ Massoud, A F; Hindmarsh, P C; Brook, C G (1996). "Hexarelin-induced growth hormone, cortisol, and prolactin release: a dose-response study.". The Journal of Clinical Endocrinology (The Endocrine Society) 81 (12): 4338–4341.  
  14. ^ a b Arvat, Emanuela; Vito, Lidia Di; Gianotti, Laura; Ramunni, Josefina; Boghen, Muni F.; Deghenghi, Romano; Camanni, Franco; Ghigo, Ezio (1997). "Mechanisms underlying the negative growth hormone (GH)". Metabolism (Elsevier BV) 46 (1): 83–88.  
  15. ^ Arvat, Emanuela; Gianotti, Laura; Vito, Lidia Di; Imbimbo, Bruno P.; Lenaerts, Vincent; Deghenghi, Romano; Camanni, Franco; Ghigo, Ezio (1995). "Modulation of Growth Hormone-Releasing Activity of Hexarelin in Man". Neuroendocrinology (S. Karger (AG)) 61 (1): 51–56.  
  16. ^ Massoud, Ahmed F.; Hindmarsh, Peter C.; Brook, Charles G. D. (1995). "Hexarelin induced growth hormone release is influenced by exogenous growth hormone". Clinical Endocrinology (Wiley-Blackwell) 43 (5): 617–621.  
  17. ^ Richard Owusu-Apenten (23 June 2010). Bioactive Peptides: Applications for Improving Nutrition and Health. CRC Press. pp. 292–.  
  18. ^ Loche S, Colao A, Cappa M, Bellone J, Aimaretti G, Farello G, et al. (1997). "The growth hormone response to hexarelin in children: reproducibility and effect of sex steroids.". J Clin Endocrinol Metab 82 (3): 861–4.  
  19. ^ Loche, S; Cambiaso, P; Carta, D; Setzu, S; Imbimbo, B P; Borrelli, P; Pintor, C; Cappa, M (1995). "The growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, in short normal and obese children and in hypopituitary subjects.". The Journal of Clinical Endocrinology (The Endocrine Society) 80 (2): 674–678.  
  20. ^ Bellone, J; Aimaretti, G; Bartolotta, E; Benso, L; Imbimbo, B P; Lenhaerts, V; Deghenghi, R; Camanni, F; Ghigo, E (1995). "Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, before and during puberty.". The Journal of Clinical Endocrinology (The Endocrine Society) 80 (4): 1090–1094.  
  21. ^ Rahim A, O'Neill PA, Shalet SM (1998). "Growth hormone status during long-term hexarelin therapy". J. Clin. Endocrinol. Metab. 83 (5): 1644–9.  
  22. ^ Ezio Ghigo (1999). Growth Hormone Secretagogues: Basic Findings and Clinical Implications. Elsevier. pp. 178–.  
  23. ^ Wiesmann UN, DiDonato S, Herschkowitz NN (1975). "Effect of chloroquine on cultured fibroblasts: release of lysosomal hydrolases and inhibition of their uptake.". Biochem Biophys Res Commun 66 (4): 1338–43.  
  24. ^ Suckling K (2006). "Discontinued drugs in 2005: cardiovascular drugs.". Expert Opin Investig Drugs 15 (11): 1299–308.  
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