Examorelin

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Examorelin
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Clinical data
Other namesL-Histidyl-2-methyl-D-tryptophyl-L-alanyl-L-tryptophyl-D-phenylalanyl-L-lysinamide
Routes of
administration		Intravenous, subcutaneous, intranasal, oral[1]
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  • None
Pharmacokinetic data
Elimination half-life~55 minutes[2]
Identifiers
  • (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
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Chemical and physical data
FormulaC47H58N12O6
Molar mass887.059 g·mol−1
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  • CC1=C(C2=CC=CC=C2N1)C[C@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC3=CNC4=CC=CC=C43)C(=O)N[C@H](CC5=CC=CC=C5)C(=O)N[C@@H](CCCCN)C(=O)N)NC(=O)[C@H](CC6=CNC=N6)N
  • InChI=1S/C47H58N12O6/c1-27-34(33-15-7-9-17-37(33)54-27)23-41(58-44(62)35(49)22-31-25-51-26-53-31)45(63)55-28(2)43(61)57-40(21-30-24-52-36-16-8-6-14-32(30)36)47(65)59-39(20-29-12-4-3-5-13-29)46(64)56-38(42(50)60)18-10-11-19-48/h3-9,12-17,24-26,28,35,38-41,52,54H,10-11,18-23,48-49H2,1-2H3,(H2,50,60)(H,51,53)(H,55,63)(H,56,64)(H,57,61)(H,58,62)(H,59,65)/t28-,35-,38-,39+,40-,41+/m0/s1
  • Key:RVWNMGKSNGWLOL-GIIHNPQRSA-N
Data page
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Examorelin (INN; also known as hexarelin; developmental codes EP-23905 and MF-6003) is a potent, 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. These GH-releasing peptides have no sequence similarity to ghrelin, but mimic ghrelin by acting as agonists at the ghrelin receptor.[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 ethinylestradiol, 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]

See also

References

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  1. ^ Page Module:Citation/CS1/styles.css has no content.Ghigo E, Arvat E, Gianotti L, Imbimbo BP, Lenaerts V, Deghenghi R, Camanni F (March 1994). "Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal, and oral administration in man". The Journal of Clinical Endocrinology and Metabolism. 78 (3): 693–698. doi:10.1210/jcem.78.3.8126144. PMID 8126144.
  2. ^ a b c d e Page Module:Citation/CS1/styles.css has no content.Imbimbo BP, Mant T, Edwards M, Amin D, Dalton N, Boutignon F, et al. (1994). "Growth hormone-releasing activity of hexarelin in humans. A dose-response study". European Journal of Clinical Pharmacology. 46 (5): 421–425. doi:10.1007/bf00191904. PMID 7957536. S2CID 19573322.
  3. ^ Page Module:Citation/CS1/styles.css has no content.Ganellin CR, Triggle DJ (21 November 1996). Dictionary of Pharmacological Agents. CRC Press. pp. 617–. ISBN 978-0-412-46630-4.
  4. ^ Page Module:Citation/CS1/styles.css has no content.Morton IK, Hall JM (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 117–. ISBN 978-94-011-4439-1.
  5. ^ a b Page Module:Citation/CS1/styles.css has no content.Moulin A, Ryan J, Martinez J, Fehrentz JA (September 2007). "Recent developments in ghrelin receptor ligands". ChemMedChem. 2 (9): 1242–1259. doi:10.1002/cmdc.200700015. PMID 17520591. S2CID 24945528.
  6. ^ a b c Page Module:Citation/CS1/styles.css has no content.Wang Y, Tomlinson B (March 2009). "Tesamorelin, a human growth hormone releasing factor analogue". Expert Opinion on Investigational Drugs. 18 (3): 303–310. doi:10.1517/13543780802707658. PMID 19243281. S2CID 71177320.
  7. ^ Page Module:Citation/CS1/styles.css has no content.Carpino PA (2002). "Recent developments in ghrelin receptor (GHS-R1a) agonists and antagonists". Expert Opinion on Therapeutic Patents. 12 (11): 1599–1618. doi:10.1517/13543776.12.11.1599. S2CID 83645573.
  8. ^ a b Page Module:Citation/CS1/styles.css has no content.Arvat E, di Vito L, Maccagno B, Broglio F, Boghen MF, Deghenghi R, et al. (1997). "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. 18 (6): 885–891. doi:10.1016/s0196-9781(97)00016-8. PMID 9285939. S2CID 25480336.
  9. ^ Page Module:Citation/CS1/styles.css has no content.Ghigo E, Arvat E, Gianotti L, Grottoli S, Rizzi G, Ceda GP, et al. (October 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. 135 (4): 407–412. doi:10.1530/eje.0.1350407. PMID 8921821.
  10. ^ Page Module:Citation/CS1/styles.css has no content.Laron Z, Frenkel J, Deghenghi R, Anin S, Klinger B, Silbergeld A (November 1995). "Intranasal administration of the GHRP hexarelin accelerates growth in short children". Clinical Endocrinology. 43 (5): 631–635. doi:10.1111/j.1365-2265.1995.tb02929.x. PMID 8548949. S2CID 30980163.
  11. ^ Page Module:Citation/CS1/styles.css has no content.Frenkel J, Silbergeld A, Deghenghi R, Laron Z (1995). "Short term effect of intranasal administration of hexarelin--a synthetic growth hormone-releasing peptide. Preliminary communication". Journal of Pediatric Endocrinology & Metabolism. 8 (1): 43–45. doi:10.1515/jpem.1995.8.1.43. PMID 7584696. S2CID 6791525.
  12. ^ Page Module:Citation/CS1/styles.css has no content.Maccario M, Arvat E, Procopio M, Gianotti L, Grottoli S, Imbimbo BP, et al. (January 1995). "Metabolic modulation of the growth hormone-releasing activity of hexarelin in man". Metabolism. 44 (1): 134–138. doi:10.1016/0026-0495(95)90300-3. PMID 7854159.
  13. ^ Page Module:Citation/CS1/styles.css has no content.Massoud AF, Hindmarsh PC, Brook CG (December 1996). "Hexarelin-induced growth hormone, cortisol, and prolactin release: a dose-response study". The Journal of Clinical Endocrinology and Metabolism. 81 (12): 4338–4341. doi:10.1210/jcem.81.12.8954038. PMID 8954038.
  14. ^ a b Page Module:Citation/CS1/styles.css has no content.Arvat E, Di Vito L, Gianotti L, Ramunni J, Boghen MF, Deghenghi R, et al. (January 1997). "Mechanisms underlying the negative growth hormone (GH) autofeedback on the GH-releasing effect of hexarelin in man". Metabolism. 46 (1): 83–88. doi:10.1016/s0026-0495(97)90173-6. PMID 9005975.
  15. ^ Page Module:Citation/CS1/styles.css has no content.Arvat E, Gianotti L, Di Vito L, Imbimbo BP, Lenaerts V, Deghenghi R, et al. (January 1995). "Modulation of growth hormone-releasing activity of hexarelin in man". Neuroendocrinology. 61 (1): 51–56. doi:10.1159/000126827. PMID 7731498.
  16. ^ Page Module:Citation/CS1/styles.css has no content.Massoud AF, Hindmarsh PC, Brook CG (November 1995). "Hexarelin induced growth hormone release is influenced by exogenous growth hormone". Clinical Endocrinology. 43 (5): 617–621. doi:10.1111/j.1365-2265.1995.tb02927.x. PMID 8548947. S2CID 31571160.
  17. ^ Page Module:Citation/CS1/styles.css has no content.Owusu-Apenten R (23 June 2010). "Anabolic Dysfunction". Bioactive Peptides: Applications for Improving Nutrition and Health. CRC Press. pp. 292–. ISBN 978-1-4398-1363-8.
  18. ^ Page Module:Citation/CS1/styles.css has no content.Loche S, Colao A, Cappa M, Bellone J, Aimaretti G, Farello G, et al. (March 1997). "The growth hormone response to hexarelin in children: reproducibility and effect of sex steroids". The Journal of Clinical Endocrinology and Metabolism. 82 (3): 861–864. doi:10.1210/jcem.82.3.3795. PMID 9062497.
  19. ^ Page Module:Citation/CS1/styles.css has no content.Loche S, Cambiaso P, Carta D, Setzu S, Imbimbo BP, Borrelli P, et al. (February 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 and Metabolism. 80 (2): 674–678. doi:10.1210/jcem.80.2.7852535. PMID 7852535.
  20. ^ Page Module:Citation/CS1/styles.css has no content.Bellone J, Aimaretti G, Bartolotta E, Benso L, Imbimbo BP, Lenhaerts V, et al. (April 1995). "Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, before and during puberty". The Journal of Clinical Endocrinology and Metabolism. 80 (4): 1090–1094. doi:10.1210/jcem.80.4.7714074. PMID 7714074.
  21. ^ Page Module:Citation/CS1/styles.css has no content.Rahim A, O'Neill PA, Shalet SM (May 1998). "Growth hormone status during long-term hexarelin therapy". The Journal of Clinical Endocrinology and Metabolism. 83 (5): 1644–1649. doi:10.1210/jcem.83.5.4812. PMID 9589671.
  22. ^ Page Module:Citation/CS1/styles.css has no content.Ghigo E (1999). Growth Hormone Secretagogues: Basic Findings and Clinical Implications. Elsevier. pp. 178–. ISBN 978-0-444-82933-7.
  23. ^ Page Module:Citation/CS1/styles.css has no content.Suckling K (November 2006). "Discontinued drugs in 2005: cardiovascular drugs". Expert Opinion on Investigational Drugs. 15 (11): 1299–1308. doi:10.1517/13543784.15.11.1299. PMID 17040192. S2CID 21632578.

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