Examorelin

Last updated
Examorelin
Hexarelin structure.png
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]
ATC code
  • 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
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
Chemical and physical data
Formula C47H58N12O6
Molar mass 887.059 g·mol−1
3D model (JSmol)
  • 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

Examorelin (INN) (developmental code names EP-23905, MF-6003), also known as hexarelin, 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

Related Research Articles

<span class="mw-page-title-main">Growth hormone</span> Peptide hormone that stimulates growth, cell reproduction and cell regeneration

Growth hormone (GH) or somatotropin, also known as human growth hormone in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in human development. GH also stimulates production of IGF-1 and increases the concentration of glucose and free fatty acids. It is a type of mitogen which is specific only to the receptors on certain types of cells. GH is a 191-amino acid, single-chain polypeptide that is synthesized, stored and secreted by somatotropic cells within the lateral wings of the anterior pituitary gland.

<span class="mw-page-title-main">Arcuate nucleus</span>

The arcuate nucleus of the hypothalamus is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several important and diverse populations of neurons that help mediate different neuroendocrine and physiological functions, including neuroendocrine neurons, centrally projecting neurons, and astrocytes. The populations of neurons found in the arcuate nucleus are based on the hormones they secrete or interact with and are responsible for hypothalamic function, such as regulating hormones released from the pituitary gland or secreting their own hormones. Neurons in this region are also responsible for integrating information and providing inputs to other nuclei in the hypothalamus or inputs to areas outside this region of the brain. These neurons, generated from the ventral part of the periventricular epithelium during embryonic development, locate dorsally in the hypothalamus, becoming part of the ventromedial hypothalamic region. The function of the arcuate nucleus relies on its diversity of neurons, but its central role is involved in homeostasis. The arcuate nucleus provides many physiological roles involved in feeding, metabolism, fertility, and cardiovascular regulation.

<span class="mw-page-title-main">Ghrelin</span> Peptide hormone involved in appetite regulation

Ghrelin is a hormone produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrelin are highest before meals when hungry, returning to lower levels after mealtimes. Ghrelin may help prepare for food intake by increasing gastric motility and stimulating the secretion of gastric acid.

<span class="mw-page-title-main">Motilin</span>

Motilin is a 22-amino acid polypeptide hormone in the motilin family that, in humans, is encoded by the MLN gene.

Growth hormone–releasing hormone (GHRH), also known as somatocrinin or by several other names in its endogenous forms and as somatorelin (INN) in its pharmaceutical form, is a releasing hormone of growth hormone (GH). It is a 44-amino acid peptide hormone produced in the arcuate nucleus of the hypothalamus.

Growth hormone-binding protein (GHBP) is a soluble carrier protein for growth hormone (GH). The full range of functions of GHBP remains to be determined however, current research suggests that the protein is associated with regulation of the GH availability and half-life in the circulatory system, as well as modulating GH receptor function.

<span class="mw-page-title-main">Growth hormone secretagogue receptor</span> Protein-coding gene in the species Homo sapiens

Growth hormone secretagogue receptor(GHS-R), also known as ghrelin receptor, is a G protein-coupled receptor that binds growth hormone secretagogues (GHSs), such as ghrelin, the "hunger hormone". The role of GHS-R is thought to be in regulating energy homeostasis and body weight. In the brain, they are most highly expressed in the hypothalamus, specifically the ventromedial nucleus and arcuate nucleus. GSH-Rs are also expressed in other areas of the brain, including the ventral tegmental area, hippocampus, and substantia nigra. Outside the central nervous system, too, GSH-Rs are also found in the liver, in skeletal muscle, and even in the heart.

<span class="mw-page-title-main">GHRP-6</span> Chemical compound

Growth hormone-releasing peptide 6 (GHRP-6), also known as growth hormone-releasing hexapeptide, is one of several synthetic met-enkephalin analogues that include unnatural D-amino acids, were developed for their growth hormone-releasing activity and are called growth hormone secretagogues. They lack opioid activity but are potent stimulators of growth hormone (GH) release. These secretagogues are distinct from growth hormone releasing hormone (GHRH) in that they share no sequence relation and derive their function through activation of a completely different receptor. This receptor was originally called the growth hormone secretagogue receptor (GHSR), but due to subsequent discoveries, the hormone ghrelin is now considered the receptor's natural endogenous ligand, and it has been renamed as the ghrelin receptor. Therefore, these GHSR agonists act as synthetic ghrelin mimetics.

<span class="mw-page-title-main">Growth-hormone-releasing hormone receptor</span> Receptor protein that binds with somatcrinin

The growth-hormone-releasing hormone receptor (GHRHR) is a G-protein-coupled receptor that binds growth hormone-releasing hormone. The GHRHR activates a Gs protein that causes a cascade of cAMP via adenylate cyclase. GHRHR is distinct from the growth hormone secretagogue receptor, where growth hormone releasing peptides act to release growth hormone.

CJC-1295, also known as DAC:GRF, is a synthetic analogue of growth hormone-releasing hormone (GHRH) and a growth hormone secretagogue (GHS) which was developed by ConjuChem Biotechnologies. It is a modified form of GHRH (1-29) with improved pharmacokinetics, especially in regard to half-life.

<span class="mw-page-title-main">Ibutamoren</span> Experimental drug

Ibutamoren is a potent, long-acting, orally-active, selective, and non-peptide agonist of the ghrelin receptor and a growth hormone secretagogue, mimicking the growth hormone (GH)-stimulating action of the endogenous hormone ghrelin. It has been shown to increase the secretion of several hormones including GH and insulin-like growth factor 1 (IGF-1) and produces sustained increases in the plasma levels of these hormones without affecting cortisol levels.

<span class="mw-page-title-main">Tabimorelin</span> Chemical compound

Tabimorelin (INN) is a drug which acts as a potent, orally-active agonist of the ghrelin/growth hormone secretagogue receptor (GHSR) and growth hormone secretagogue, mimicking the effects of the endogenous peptide agonist ghrelin as a stimulator of growth hormone (GH) release. It was one of the first GH secretagogues developed and is largely a modified polypeptide, but it is nevertheless orally-active in vivo. Tabimorelin produced sustained increases in levels of GH and insulin-like growth factor 1 (IGF-1), along with smaller transient increases in levels of other hormones such as adrenocorticotropic hormone (ACTH), cortisol, and prolactin. However actual clinical effects in adults with growth hormone deficiency were limited, with only the most severely GH-deficient patients showing significant benefit, and tabimorelin was also found to act as a CYP3A4 inhibitor which could cause it to have undesirable interactions with other drugs.

Cyril Y. Bowers, M.D., emeritus professor of medicine at Tulane University School of Medicine, attended medical school at the University of Oregon and did an internship at the University of Washington. He then studied biochemistry at Cornell University and attended the postgraduate school of medicine at the University of Pennsylvania. From 1961-2004 he was the director of the Section of Endocrinology & Metabolism in the department of medicine at Tulane University School of Medicine. Bowers has served on the editorial board of several endocrine journals, was a member of the National Institute of Diabetes and Digestive and Kidney Diseases Study Section for eight years and has written over 400 articles in peer-reviewed journals, including chapters in books and over 200 abstracts.

Modified GRF (1-29) often abbreviated as mod GRF (1-29), originally known as tetrasubstituted GRF (1-29), is a term used to identify a 29 amino acid peptide analogue of growth-hormone-releasing hormone (GHRH), a releasing hormone of growth hormone (GH). It is a modified version of the shortest fully functional fragment of GHRH, often referred to as growth hormone releasing factor (1-29), and also known by its standardized name, sermorelin.

Growth hormone secretagogues or GH secretagogues (GHSs) are a class of drugs which act as secretagogues of growth hormone (GH). They include agonists of the ghrelin/growth hormone secretagogue receptor (GHSR), such as ghrelin (lenomorelin), pralmorelin (GHRP-2), GHRP-6, examorelin (hexarelin), ipamorelin, and ibutamoren (MK-677), and agonists of the growth hormone-releasing hormone receptor (GHRHR), such as growth hormone-releasing hormone, CJC-1295, sermorelin, and tesamorelin.

<span class="mw-page-title-main">Tesamorelin</span> Pharmaceutical drug

Tesamorelin (INN) is a synthetic form of growth-hormone-releasing hormone (GHRH) which is used in the treatment of HIV-associated lipodystrophy, approved initially in 2010. It is produced and developed by Theratechnologies, Inc. of Canada. The drug is a synthetic peptide consisting of all 44 amino acids of human GHRH with the addition of a trans-3-hexenoic acid group.

<span class="mw-page-title-main">Macimorelin</span> Chemical compound

Macimorelin (INN) – or Macrilen – is a drug that was developed by Æterna Zentaris for use in the diagnosis of adult growth hormone deficiency. Macimorelin acetate, the salt formulation, is a synthetic growth hormone secretagogue receptor agonist. It is a growth hormone secretagogue receptor agonist causing release of growth hormone from the pituitary gland. Macimorelin acetate is described chemically as D-Tryptophanamide, 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-acetate.

<span class="mw-page-title-main">Pralmorelin</span> Chemical compound

Pralmorelin (INN), also known as pralmorelin hydrochloride (JAN) and pralmorelin dihydrochloride (USAN), as well as, notably, growth hormone-releasing peptide 2 (GHRP-2), is a growth hormone secretagogue (GHS) used as a diagnostic agent that is marketed by Kaken Pharmaceutical in Japan in a single-dose formulation for the assessment of growth hormone deficiency (GHD).

<span class="mw-page-title-main">Ipamorelin</span> Peptide selective agonist of the ghrelin/growth hormone secretagogue receptor

Ipamorelin (INN) (developmental code name NNC 26-0161) is a peptide selective agonist of the ghrelin/growth hormone secretagogue receptor (GHS) and a growth hormone secretagogue. It is a pentapeptide with the amino acid sequence Aib-His-D-2-Nal-D-Phe-Lys-NH2 that was derived from GHRP-1.

<span class="mw-page-title-main">Ulimorelin</span> Chemical compound

Ulimorelin is a drug with a modified cyclic peptide structure which acts as a selective agonist of the ghrelin/growth hormone secretagogue receptor (GHSR-1a).. Unlike many related drugs, ulimorelin has little or no effect on growth hormone (GH) release in rats. However, like ghrelin and other ghrelin agonists, ulimorelin does stimulate GH release with concomitant increases in insulin-like growth factor 1 (IGF-1) in humans. It has been researched for enhancing gastrointestinal motility, especially in gastroparesis and in aiding recovery of bowel function following gastrointestinal surgery, where opioid analgesic drugs used for post-operative pain relief may worsen existing constipation. While ulimorelin has been shown to increase both upper and lower gastrointestinal motility in rats, and showed promising results initially in humans, it failed in pivotal clinical trials in post operative ileus.

References

  1. ↑ 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. 1 2 3 4 5 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. ↑ Ganellin CR, Triggle DJ (21 November 1996). Dictionary of Pharmacological Agents. CRC Press. pp. 617–. ISBN   978-0-412-46630-4.
  4. ↑ 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. 1 2 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. 1 2 3 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. ↑ 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. 1 2 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. ↑ 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. ↑ 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. ↑ 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. ↑ 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. ↑ 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. 1 2 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. ↑ 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. ↑ 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. ↑ 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. ↑ 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. ↑ 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. ↑ 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. ↑ 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. ↑ Ghigo E (1999). Growth Hormone Secretagogues: Basic Findings and Clinical Implications. Elsevier. pp. 178–. ISBN   978-0-444-82933-7.
  23. ↑ 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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