Hexarelin, also known by its International Nonproprietary Name (INN) Examorelin, is a synthetic hexapeptide belonging to the class of growth hormone-releasing peptides (GHRPs). Developed by Mediolanum Farmaceutici under developmental code names EP-23905 and MF-6003, hexarelin represents a potent and highly selective agonist of the ghrelin/growth hormone secretagogue receptor (GHSR).
Chemical Structure and Composition
Hexarelin is a hexapeptide with the specific amino acid sequence His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2. This synthetic peptide was derived from GHRP-6 (Growth Hormone Releasing Peptide-6) through structural modifications designed to enhance its biological activity and selectivity.
The molecular formula is represented as:
- 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
- SMILES: CC1=C(C2=CC=CC=C2N1)CC@HNC(=O)C@HN
Mechanism of Action
Primary Mechanism
Hexarelin functions as a potent synthetic peptidic agonist of the ghrelin/growth hormone secretagogue receptor (GHSR). Despite having no structural similarity to ghrelin, hexarelin mimics ghrelin’s biological effects by binding to and activating the same receptor system.
The peptide operates through multiple pathways:
- Ghrelin Receptor Activation (GHS-R1a): Enhances appetite, GH release, and fat metabolism
- Pituitary Stimulation: Signals directly to release growth hormone from anterior pituitary somatotrophs
- Hypothalamic Action: Acts on hypothalamic neurons to coordinate the growth hormone response
Cellular Mechanisms
Activation of GHS-R by hexarelin leads to stimulation of phospholipase C and production of inositol 1,4,5-trisphosphate. This cascade ultimately results in increased intracellular calcium levels and subsequent growth hormone release.
Pharmacological Properties
Growth Hormone Release
Hexarelin demonstrates substantial and dose-dependent increases in plasma levels of growth hormone (GH) in both animal models and human subjects. Notably, hexarelin releases more GH than does growth hormone-releasing hormone (GHRH) in humans, establishing its superior potency.
When combined with GHRH, hexarelin produces synergistic effects on GH release, resulting in “massive” increases in plasma GH levels even at low doses.
Additional Hormonal Effects
Beyond growth hormone stimulation, hexarelin influences several other hormonal systems:
- Prolactin: Slightly and dose-dependently stimulates prolactin release
- ACTH: Dose-dependent stimulation of adrenocorticotropic hormone
- Cortisol: Dose-dependent cortisol elevation
Importantly, hexarelin does not affect plasma levels of glucose, luteinizing hormone (LH), follicle-stimulating hormone (FSH), or thyroid-stimulating hormone (TSH), indicating specificity in its hormonal actions.
IGF-1 Effects
Research presents conflicting data regarding hexarelin’s effects on insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 1 (IGFBP-1). Some studies finding no increase and others finding a slight yet statistically significant increase in these parameters.
Administration Routes and Bioavailability
Hexarelin demonstrates versatility in administration methods, being orally-active and centrally-penetrant. Clinical studies have evaluated effectiveness through:
- Intravenous administration
- Subcutaneous injection
- Intranasal delivery
- Oral administration
This multi-route accessibility represents a significant advantage over many peptide therapeutics that require injection.
Clinical Applications and Research
Therapeutic Development
Hexarelin reached phase II clinical trials for the treatment of growth hormone deficiency and congestive heart failure but did not complete development and was never commercially marketed.
Cardiovascular Effects
Research indicates that hexarelin might have cardiovascular actions due to the peripheral distribution of GHSR in heart and blood vessels, extending beyond its primary growth hormone-releasing properties.
Muscle and Body Composition Effects
Regulatory and Modulatory Factors
Tolerance Development
A partial and reversible tolerance to the GH-releasing effects of hexarelin occurs in humans with long-term administration (50–75% decrease in efficacy over the course of weeks to months). This tolerance pattern represents a significant consideration for therapeutic applications.
Hormonal Modulation
Several factors influence hexarelin’s effectiveness:
- Sex Steroids: Testosterone, testosterone enanthate, and ethinylestradiol significantly potentiate the GH-releasing effects
- Puberty: Significantly augment the GH-elevating actions due to increased sex steroid levels
- Growth Hormone Feedback: Pre-administration of GH blunts the GH-releasing effect
- IGF-1 Feedback: Pre-treatment with IGF-1 also blunts the GH-elevating effect
Comparison to Related Peptides
Structural Derivatives
Hexarelin represents an evolution from GHRP-6, with structural modifications that enhance potency and selectivity. Its primary mechanism is the stimulation of growth hormone (GH) release from the pituitary gland by mimicking ghrelin, positioning it among the most potent growth hormone secretagogues available.
Receptor Binding
Safety and Contraindications
While hexarelin demonstrated acceptable safety profiles in clinical trials, the development was discontinued before reaching market approval. The tolerance development and potential for desensitization represent primary concerns for long-term therapeutic use.
Research Applications
Current Status
Originally developed for research purposes, Hexarelin has gained attention among researchers studying growth hormone physiology and potential therapeutic applications.
Experimental Uses
Beyond growth hormone research, studies have investigated hexarelin’s effects on:
- Cardiovascular function
- Neuroprotection
- Metabolic regulation
- Muscle physiology
Analytical Considerations
Hexarelin is an engineered growth-hormone-releasing peptide (GHRP), specifically a hexapeptide (His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2), that functions via particular receptors in the pituitary and hypothalamus regions to induce growth hormone production in both animals and humans.
Conclusion
Hexarelin represents a significant advancement in synthetic growth hormone secretagogue development. Its potent activity, multiple administration routes, and specific receptor targeting mechanisms established it as a valuable research tool and potential therapeutic agent. While clinical development was ultimately discontinued, hexarelin continues to provide important insights into growth hormone physiology and peptide-based therapeutic approaches. The peptide’s unique properties, including its ability to cross the blood-brain barrier and maintain oral bioactivity, distinguish it from many other peptide-based compounds. However, the development of tolerance and incomplete clinical development highlight the complexities involved in translating peptide research into therapeutic applications.