Description
Summary Abstract
Hexarelin (Examorelin; His-D-2-MeTrp-Ala-Trp-D-Phe-Lys-NH₂; CAS 140703-51-1) is a synthetic hexapeptide growth hormone secretagogue (GHS) developed by Mediolanum Farmaceutici as a structural analog of growth hormone-releasing peptide-6 (GHRP-6). The single-residue modification — substitution of D-Trp at position 2 with D-2-methyltryptophan — substantially increases binding affinity for the growth hormone secretagogue receptor type 1a (GHS-R1a, ghrelin receptor) and extends metabolic stability versus the parent compound. Among the classical hexapeptide GHS family (GHRP-2, GHRP-6, Hexarelin), Hexarelin elicits the most robust acute growth hormone (GH) release per dose in preclinical studies. A mechanistically distinct property is direct binding to the cardiac scavenger receptor CD36, producing cardioprotective effects independent of GH or IGF-1 axis stimulation and characterizing Hexarelin as uniquely suited for cardiac biology research applications.
Clinical Indications
Hexarelin is investigated across growth hormone biology and cardiac research contexts:
- GH Axis Stimulation: Highest acute GH-releasing potency among classical hexapeptide GHRPs; used in hypothalamic-pituitary axis studies, GH secretion kinetics, and comparison with GHRP-2, GHRP-6, and ipamorelin for receptor pharmacology research.
- Cardioprotection: GHS-R1a-independent cardioprotective effects have been documented via CD36 binding, including protection against ischemia-reperfusion injury, improvements in cardiac contractility, and favorable effects on cardiac remodeling in preclinical models — a unique feature relative to other GHRPs.
- GH Deficiency / Somatotropic Axis Research: Preclinical and early clinical studies established Hexarelin’s capacity to normalize GH pulsatility in GH-deficient states; it served as the foundational compound for GHS pharmacology characterization by Arvat, Ghigo, and Coiro groups in the 1990s–2000s.
Contraindications
- Receptor Desensitization: Repeated Hexarelin administration produces partial, reversible GHS-R1a desensitization not seen with ipamorelin; longitudinal in vivo studies should include washout periods and receptor expression assessments to manage this variable.
- Cortisol and ACTH Stimulation: Unlike GHRP-2 and ipamorelin, Hexarelin at higher doses stimulates ACTH and cortisol release in addition to GH; studies with adrenocortical endpoints must control for this off-target secretagogue effect.
- Ghrelin Pathway Overlap: Hexarelin activates GHS-R1a in common with endogenous ghrelin; experiments using Hexarelin as a GHS-R1a tool compound should include ghrelin receptor-null controls to deconvolve receptor-specific from non-specific pharmacology.
Mechanism of Action (MOA)
Hexarelin operates through two independent receptor systems, conferring both somatotropic and cardiac pharmacology:
GHS-R1a (Ghrelin Receptor) Agonism
Hexarelin binds and activates GHS-R1a at the pituitary and hypothalamus with higher affinity than GHRP-6, driving GH release through phospholipase C activation, IP3-mediated Ca²⁺ mobilization, and subsequent somatotroph stimulation. The 2-methyltryptophan substitution provides a 3D topology that improves binding geometry at GHS-R1a relative to the unmethylated D-Trp of GHRP-6.
CD36 Cardioprotection
Independent of GHS-R1a, Hexarelin binds the cardiac scavenger receptor CD36, a mechanism not shared by GHRP-2, GHRP-6, or ipamorelin. This unique receptor interaction mediates cardioprotective effects including anti-ischemic protection, positive inotropic effects, and modulation of cardiac fibrosis — positioning Hexarelin as a dual-mechanism tool compound for cardiovascular research.
Hypothalamic GHRH Amplification
In addition to direct pituitary GHS-R1a activation, Hexarelin enhances hypothalamic growth hormone-releasing hormone (GHRH) release, producing a synergistic GH response when co-administered with GHRH analogs. This two-level amplification of the somatotropic axis is relevant for GH dynamics research in hypopituitary and aging models.
ACTH/Cortisol Pathway
At pharmacologically relevant doses, Hexarelin also activates ACTH and cortisol secretion through mechanisms independent of its GH-releasing activity — an effect not observed with ipamorelin. This broader hypothalamic-pituitary-adrenal (HPA) axis stimulation should be considered in study designs with adrenal or stress endpoints.
Key Features & Specifications
Hexarelin is supplied as a 10 mg lyophilized hexapeptide powder for GH axis and cardioprotection research:
Chemical Analysis
| Property | Specification Reference Data |
|---|---|
| Sequence | His-D-2-MeTrp-Ala-Trp-D-Phe-Lys-NH₂ |
| IUPAC Name | L-histidyl-D-2-methyltryptophyl-alanyl-L-tryptophyl-D-phenylalanyl-L-lysinamide |
| CAS Number | 140703-51-1 |
| Molecular Formula | C47H58N12O6 |
| Molecular Weight | 887.04 g/mol |
| PubChem CID | 6918297 |
| Synonyms | Examorelin; Hexarelin acetate; GHRP-6 analogue; EP-23905; MF-6003 |
| Form / Variation | 10 MG Lyophilized Powder (SKU P-056, $68.00) |
Storage, Safety, and Handling
Storage Protocol
Store lyophilized Hexarelin at −20 °C, protected from light and moisture. Upon reconstitution in sterile bacteriostatic water or 0.9% saline, store at 4 °C for up to 7 days and aliquot to avoid repeated freeze-thaw. The 2-methyltryptophan substitution provides greater chemical stability than GHRP-6 under standard handling conditions; confirm peptide integrity by HPLC before extended in vivo use.
Handling & Compliance
Handle with standard PPE. Hexarelin (Examorelin) is not approved for therapeutic use in any jurisdiction. It is listed as a prohibited substance by the World Anti-Doping Agency (WADA) under the growth hormone secretagogues category. Institutional compliance and animal care protocol review are required for all in vivo research applications.