GHRP-6: Hexapeptide Chemistry, Receptor Structure and Published Data

GHRP-6 is the hexapeptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2, described by Bowers and colleagues in 1984 and also indexed as SK&F 110679, U-75799E and [His1, Lys6]-GHRP. Its formula is C46H56N12O6, its molecular weight 873.0 g/mol and its monoisotopic mass 872.4446 Da, under CAS number 87616-84-0 and PubChem CID 9919153.

Two of the six positions carry D-configured residues, D-tryptophan at position 2 and D-phenylalanine at position 5, and the C-terminus is an amide rather than a free acid. Those departures from ordinary L-peptide chemistry are what let the molecule survive exopeptidase exposure long enough to be measured in circulation. The two indole side chains contributed by tryptophan at positions 2 and 4 dominate the ultraviolet absorbance profile and push the computed polar surface area to 301 square angstroms across 23 rotatable bonds.

The molecule has a documented origin in opioid peptide chemistry. Bowers and Momany derived the growth hormone releasing peptide series from met-enkephalin analogues that had lost opioid activity while retaining secretagogue activity at the pituitary. GHRP-6 therefore existed as a defined pharmacological tool for fifteen years before its endogenous counterpart was known: the receptor was cloned in 1996 and ghrelin isolated in 1999. That ordering is why older literature names the receptor after the synthetic class rather than the natural hormone.

GHRP-6 binds the growth hormone secretagogue receptor 1a, a class A G protein-coupled receptor. Wang and colleagues resolved that complex by cryo-electron microscopy in 2021 at 3.2 angstroms with a Gq heterotrimer, deposited as PDB 7F9Z, alongside a companion ghrelin-bound structure at 2.9 angstroms deposited as 7F9Y.

The pocket contacting the hexapeptide is lined by F279 (6.51), F309 (7.39), F312 (7.42) and Y313 (7.43), an aromatic cluster that accommodates the two indole rings and the D-phenylalanine. R283 (6.55) forms a cation-pi interaction with D-Phe5. Read as a pair, the two structures show a six-residue synthetic ligand and a 28-residue acylated hormone converging on overlapping receptor contacts.

What separates them is a second cavity. Ghrelin carries an octanoyl group on Ser3, and five of that fatty acid's eight carbons occupy a hydrophobic sub-pocket formed with F286 (6.58), I178 (4.60) and L181 (4.63). GHRP-6 has no acyl chain and leaves that cavity empty, yet still activates the receptor. The pair therefore separates contacts required for activation from those the hormone adds through its lipid modification.

Reported potency places the hexapeptide in the low nanomolar range. The IUPHAR/BPS Guide to PHARMACOLOGY entry for this receptor lists GHRP-6 as a full agonist with pEC50 values of 8.3 to 9.1 at the human receptor in calcium release and inositol phosphate accumulation assays, a pKi of 8.8 at the rat receptor, and a wider pKd span of 6.6 to 8.8 across binding preparations that reflects assay format rather than disagreement about the target.

GHRP-6 was characterized by Bowers, Momany, Reynolds and Hong in 1984 as a hexapeptide acting on the pituitary to release growth hormone without concurrent release of LH, FSH, TSH or prolactin. Minimum active concentrations in the pituitary incubate assay ran from 1 to 10 ng/mL, and growth hormone rose within 2 minutes in vivo, peaking at 10 to 20 minutes.

That first report spanned rats, monkeys, lambs and calves, an unusually wide species panel for an initial characterization, and the response held across all of them. Repeated exposure over 9 or 25 days in immature rats left pituitary responsiveness intact, indicating the somatotrope did not desensitize across that window.

The receptor itself stayed unidentified for twelve more years. Howard and colleagues reported in Science in 1996 the cloning of a G protein-coupled receptor from the pituitary and from the arcuate ventromedial and infundibular hypothalamus of swine and humans, and showed it was the target of this secretagogue class. That result converted a phenomenological pituitary assay into a defined molecular target, and the search it opened produced ghrelin three years later.

GHRP-6 has been examined across ischaemic and toxic organ injury models, largely by groups working under the development code CIGB-500. Reported endpoints are structural and molecular rather than behavioural: interstitial fibrosis, left ventricular systolic function, alveolar-capillary permeability, tubular epithelial cell survival and proteomic pathway shifts.

In a rat permanent left descending coronary artery ligation model reported in 2026, animals given the hexapeptide across 7 days after surgery showed attenuated myocardial tissue demise, reduced interstitial fibrosis and scarring, and improved left ventricle physiology against saline controls. Proteomic profiling attributed the separation to upregulated fatty acid beta-oxidation, anti-apoptotic pathways, antioxidant defences and mitochondrial metabolic reprogramming.

Three further reports extend the pattern beyond the infarct model. An earlier rat study paired the hexapeptide with doxorubicin and recorded preserved myocardial fibres, retained systolic function and upregulation of the pro-survival gene Bcl-2. In lipopolysaccharide and zymosan lung injury models in mice, it reduced neutrophilic alveolitis and lowered serum interleukin-1 beta at 24 hours. A self-assembling GHRP-6 hydrogel in acute kidney injury enriched spermidine, L-glutamine and acetyl-CoA on metabolomic sequencing and sustained tubular epithelial cell survival through the mTOR-P70 pathway.

GHRP-6 has one published human pharmacokinetic dataset. Cabrales and colleagues studied nine male volunteers in 2013 at three exposure levels of 100, 200 and 400 µg/kg, and reported bi-exponential disposition fitting with R squared above 0.99, a distribution half-life of 7.6 ± 1.9 minutes and an elimination half-life of 2.5 ± 1.1 hours.

Quantification ran down to a lower limit of 5 ng/mL, reached by 12 hours and capturing more than 85 percent of the area under the curve. Four of the nine volunteers showed atypical concentration spikes during elimination, an irregularity the authors recorded rather than resolved.

Analytical laboratories handle the hexapeptide as one of a small family that has to be told apart from close relatives. González-López and colleagues reported in 2023 that GHRP-6, GHRP-4 and sermorelin (22-29) were stable to enzymatic and blood challenge and could serve as in-house internal standards for quantifying this peptide class in biological matrices. Stability under those conditions is what qualifies a compound as a reference rather than an analyte.

Repeat-exposure toxicology exists in a non-rodent species. A 28-day beagle dog study published in 2025 under the CIGB-500 designation set the no observable adverse effect level at 2000 µg/kg per day, the highest level tested.

GHRP-6 reached a phase III readout in 2026 as one half of a two-component combination. The COURAGE-2 trial paired 75 µg of epidermal growth factor with 5 mg of the hexapeptide twice daily across 7 days in acute ischaemic stroke, enrolling 188 participants within 12 hours of symptom onset and comparing against standard care.

The trial missed its primary endpoint, with no differences in modified Rankin Scale score, Barthel Index or survival across the whole randomized cohort. A severe-stroke subgroup of 27 separated from controls, and the authors described that signal as warranting further study rather than as a conclusion.

Human in vitro work exists on a much smaller scale. Ostadian and colleagues cultured 240 human germinal vesicle oocytes across a concentration range in 2025 and identified 75 ng/mL as the most effective, giving maturation rates of 70 percent on the first day and 80 percent on the second. Gene expression analysis on a further 164 oocytes indicated nucleonic maturation without a matching shift in cytoplasmic maturation markers at 24 hours.

Non-mammalian work supplies an independent line. Rodríguez-Viera and colleagues delivered 500 µg/kg of the hexapeptide through aquafeeds to gilthead sea bream and reported stable plasma lactate, triglycerides and cortisol after an incomplete Freund's adjuvant challenge, where controls shifted. Transcriptomics showed il10, il15, il34 and mx1 raised in anterior intestine and il8, il10 and ighm in spleen, without histological damage.

Published handling figures for GHRP-6 come from supplier specifications rather than from peer-reviewed measurement. Vendors commonly list the acetate salt as a white to off-white lyophilized powder at 98 percent or higher purity by HPLC, held at minus 20 degrees Celsius. Catalogue specifications are not equivalent to lot-level analytical confirmation.

Salt form determines what a stated mass means. CAS number 87616-84-0 and PubChem CID 9919153 describe the free peptide at C46H56N12O6 and 873.0 g/mol, while material is usually supplied as the acetate, which carries a variable counter-ion and therefore a different peptide content by weight. Records should state which form a given lot is, because a gravimetric figure alone is otherwise ambiguous.

Two structural features govern what degrades first. The C-terminal amide can hydrolyse to the free acid, a one-dalton shift visible by high-resolution mass spectrometry and the most informative stability marker for this molecule. The two tryptophan indoles are most vulnerable to oxidation and photodegradation, which is why amber glass and minimal light exposure are conventional for tryptophan-rich sequences.

Identity confirmation rests on a small set of fixed values: monoisotopic mass 872.4446 Da, InChIKey WZHKXNSOCOQYQX-FUAFALNISA-N, UNII 4H7N4I6X6A and ChEMBL identifier CHEMBL105462. A computed XLogP of 1.9 with 11 hydrogen-bond donors and a polar surface area of 301 square angstroms describes a peptide that dissolves in aqueous buffer, and the two indole chromophores make reversed-phase chromatography with ultraviolet detection near 280 nanometres straightforward.