GHRP-2 (Pralmorelin): growth-hormone-releasing peptide approved in Japan
Synthetic six-amino-acid peptide that triggers the body to release growth hormone; approved in Japan to test whether the pituitary gland makes enough growth hormone; not FDA-approved.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
GHRP-2 (also known as pralmorelin, CAS 158827-34-0) is a synthetic six-amino-acid peptide that triggers the body to release growth hormone (GH). It works by binding to the ghrelin receptor (GHSR-1a) — the same receptor activated by the hunger hormone ghrelin — at both the hypothalamus and the pituitary gland, producing a strong GH pulse. GHRP-2 was developed by Polygen (Germany) and the Tulane University group led by Cyril Bowers as part of the systematic GHRP series following GHRP-6. It was approved in Japan in 2004 by the Pharmaceuticals and Medical Devices Agency (PMDA) as KP-102D (Kaken Pharmaceutical) for diagnosing impaired GH secretory reserve in adults — the only major regulatory approval the peptide has received (Drugs R&D 2004). The stored sequence HAWFK is a five-letter approximation; the actual structure is D-Ala-D-β(2-naphthyl-Ala)-Ala-Trp-D-Phe-Lys-NH₂, a hexapeptide with alternating D- and L-amino acids and a C-terminal amide — neither the D-residue encoding nor the amide cap is visible in the raw sequence.
History
GHRP-2 emerged from the same structure-activity program that produced GHRP-6. Following the discovery of GHRPs in the early 1980s, researchers sought compounds with greater potency and metabolic stability. Substituting D-β-(2-naphthyl)-alanine at position 2 (versus D-tryptophan in GHRP-6) produced a compound with substantially higher GHSR-1a affinity and GH-releasing potency (Ferro and colleagues, Drug Testing and Analysis 2016). Polygen and Tulane held the foundational patents; Kaken Pharmaceutical acquired worldwide rights and sublicensed to Wyeth for the US and Canada. Phase 3 diagnostic-use trials in Japan led to PMDA approval of KP-102D in 2004. A Phase 2 programme with Wyeth in the US for GH deficiency treatment was discontinued, and a Phase 2 programme for short stature using an intranasal formulation (KP-102LN) in Japan did not reach registration (Drugs R&D 2004).
What it does
GHRP-2 stimulates GH release by acting simultaneously at the hypothalamus (triggering GHRH release) and at pituitary somatotroph cells (directly driving GH granule exocytosis). As a full GHSR-1a agonist it preserves the pulsatile pattern of GH secretion; GH response is potentiated by co-administration of GHRH. Its principal clinical use is as a diagnostic probe: a low GH peak after IV GHRP-2 identifies patients with impaired pituitary GH secretion. Beyond GH, GHRP-2 co-stimulates ACTH and cortisol release and increases appetite — properties shared across the GHRP class and consistent with ghrelin's endogenous roles in stress responsiveness and energy balance.
Evidence
- Human (diagnostic, Phase 3, Japan): Multicentre study (n = 81 healthy volunteers, 8 obese subjects, 58 GH-deficient patients): IV pralmorelin 2 μg/kg (maximum 100 μg) administered fasting. Mean peak GH in healthy subjects: 87.34 μg/L; in GH-deficient patients: 1.34 μg/L. ROC analysis identified a peak GH cut-off of 15.0 μg/L at 60 min as the optimal threshold distinguishing GH-deficient from healthy subjects; this study formed the basis for PMDA approval (Chihara and colleagues, cited in Drugs R&D 2004).
- Human (pituitary-direct action): In 8 healthy volunteers and 11 patients with homozygous inactivating GHRH receptor mutations, IV pralmorelin 2 μg/kg raised GH from 0.59 to a peak of 46.8 μg/L in healthy subjects and from 0.11 to 0.49 μg/L in GHRH receptor-deficient patients — confirming direct pituitary action independent of GHRH signalling (Gondo and colleagues, cited in Drugs R&D 2004).
- Human (children, intranasal, Phase 2): 15 children with GH deficiency or idiopathic short stature received intranasal pralmorelin over 3–18 months; height velocity increased from 3.7 cm/year at baseline to 6.1 cm/year at 6 months and 6.0 cm/year at 18–24 months. No significant changes in IGF-1 or IGFBP-3 were observed. The programme did not proceed to registration (Pihoker and colleagues, cited in Drugs R&D 2004).
- Human (ACTH pathway): GHRP-2 stimulates ACTH and cortisol in healthy subjects. In mouse anterior pituitary cells, GHRP-2 increased intracellular cAMP; PKA inhibition (H89) and PKC inhibition (bisindolylmaleimide I) each partially blocked ACTH secretion, while POMC mRNA induction was PKA-dependent only — demonstrating dual PKA+PKC regulation of ACTH secretion with separate control of ACTH synthesis (Kageyama and colleagues, Regulatory Peptides 2009).
- In vitro / structure-activity: SAR studies confirm that D-β-(2-naphthyl)-Ala substitution at position 2 confers markedly higher GHSR-1a affinity versus GHRP-6; GHRP-2 shows a full agonist activation profile. The core Ala-Trp-(D-Phe)-Lys motif is required for receptor interaction (Ferro and colleagues, Drug Testing and Analysis 2016).
Myths and misconceptions
- "GHRP-2 is interchangeable with GHRP-6" — Both are GHSR-1a agonists but differ structurally and in potency. GHRP-2 has higher GHSR-1a affinity than GHRP-6; GHRP-6 has a longer history of human study. GHRP-2 is Japan-approved for diagnostic use; GHRP-6 has no major regulatory approval. Both share the class ACTH/cortisol co-stimulation signal.
- "GHRP-2 is approved as a treatment for GH deficiency" — The Japanese PMDA approval (KP-102D) is specifically for diagnostic use — to identify impaired GH secretory capacity — not as a therapeutic. The treatment-use programmes (Wyeth US, KP-102LN Japan) were discontinued.
- "GHRP-2 requires GHRH to work" — GHRP-2 acts directly on pituitary GHSR-1a independently of GHRH, demonstrated in patients with congenital GHRH receptor inactivation who show a partial but real GH response to IV GHRP-2.
Common questions
Why does GHRP-2 also stimulate ACTH and cortisol? GHSR-1a is expressed on corticotroph cells as well as somatotrophs. GHRP-2 binding drives cAMP production and calcium signalling in corticotrophs, leading to ACTH secretion via both PKA and PKC pathways. This reflects an endogenous role for the ghrelin axis in stress-responsive HPA activation and is a class property shared by all GHRPs at clinical doses (Kageyama and colleagues, Regulatory Peptides 2009).
What is the GH cut-off for diagnosing GH deficiency with GHRP-2? In the pivotal Japanese multicenter study, a peak GH ≤ 15.0 μg/L at 60 min after IV pralmorelin 2 μg/kg distinguished GH-deficient patients from healthy controls with the best ROC operating characteristics. This is the approved diagnostic threshold used in Japan (Drugs R&D 2004).
Known effects
- GH secretagogue (GHSR-1a full agonist) — higher potency than GHRP-6; Preclinical and human data
- Diagnostic GH stimulation test — PMDA-approved (Japan, 2004, KP-102D)
- ACTH/cortisol co-stimulation — class effect; PKA and PKC pathways; Human data
- Appetite stimulation (orexigenic) — consistent with ghrelin axis activation; expected class effect
- Height velocity improvement in children (intranasal) — Phase 2 open-label data only; not registered
Safety signals
Transient adverse events shared with the GHRP class include body warmth/flushing, borborygmus, and perspiration — all self-resolving. Appetite increase is expected given ghrelin-axis activation. Cortisol and ACTH elevations are transient and generally subclinical in healthy adults. In the diagnostic-use approval studies, no significant adverse events beyond mild transient warmth and gastrointestinal sensations were reported. The ACTH co-stimulation may be clinically relevant in patients with adrenal insufficiency. No long-term treatment safety dataset exists, as the therapeutic development programmes were discontinued (Drugs R&D 2004).
Regulatory status
- Japan: Approved as a diagnostic agent (KP-102D, Kaken Pharmaceutical) for hypothalamo-pituitary function testing (GH stimulation test). Prescription-only.
- US/EU: No regulatory approval. Phase 2 development (Wyeth) was discontinued as of 2004.
- WADA: Prohibited — S2 (peptide hormones, growth factors, related substances and mimetics) (Semenistaya and colleagues, Drug Testing and Analysis 2015).
Related peptides
See also: GHRP-6, CJC-1295, Sermorelin
Mechanism
GHRP-2's structure — D-Ala-D-β(2-Naphthyl-Ala)-Ala-Trp-D-Phe-Lys-NH₂ — features alternating D- and L-amino acids. The D-residues confer protease resistance; D-β-(2-naphthyl)-Ala at position 2 is the primary pharmacophore responsible for GHRP-2's high GHSR-1a affinity and greater potency versus GHRP-6 (D-Trp²). GHSR-1a is a constitutively active Gαq/Gαs/G11-coupled GPCR. GHRP-2 binding activates Gαq → phospholipase C → IP3/DAG → Ca²⁺ mobilisation → GH granule exocytosis from somatotrophs. A parallel Gαs → cAMP → PKA pathway augments GH secretion and mediates ACTH induction in corticotrophs via POMC gene upregulation. At the hypothalamus, GHSR-1a activation stimulates GHRH release, amplifying pituitary GH output and explaining synergistic effects with exogenous GHRH.
In mouse anterior pituitary cells, GHRP-2-induced ACTH secretion requires both PKA and PKC; POMC mRNA induction is PKA-dependent only (Kageyama and colleagues, Regulatory Peptides 2009). Pharmacokinetic data in rats show oral bioavailability approximately 0.4%, SC bioavailability approximately 41%, and a half-life of approximately 0.8 h (IV/SC). In humans, IV administration produces peak GH within 45–60 min. Metabolism occurs primarily via intestinal hydrolysis and tissue peptidases; excretion is predominantly fecal (Drugs R&D 2004).
Open questions
- Whether the Gαs/cAMP component of GHSR-1a signalling contributes meaningfully to GH release in humans relative to the Gαq/Ca²⁺ pathway at therapeutic concentrations
- Whether long-term GHRP-2 treatment in GH deficiency or short stature would provide height benefit comparable to recombinant GH, given appetite and ACTH co-stimulation constraints
- Whether the Japan-approved diagnostic threshold (peak GH ≤ 15.0 μg/L) offers comparable sensitivity and specificity to the glucagon stimulation test or insulin tolerance test used in Western markets
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
Could brief, timed doses of GHRP-2 free up enough active growth factor in critically ill patients to help their muscles and organs recover?
If true, this could give intensive care doctors a new tool to fight the severe muscle wasting seen after major surgery or serious illness. Unlike continuous growth hormone, which has caused harm in ICU trials, a short pulse might offer the benefit without the risk.
Does lysine work as a precise geometric key rather than a simple electrical glue for GHRP-2 binding?
If true, drug designers could use this rule to build longer-lasting growth hormone drugs that keep the right shape without the easily-chopped-off lysine tail. This would matter for patients who need stable, predictable growth hormone therapy.
Can changing the size and electron character of the aromatic ring at position 2 predictably dial GHRP-2's potency up or down?
If true, chemists could design a family of GHRP-2-like molecules spanning a wide range of strengths, selecting a weaker version for routine diagnostic testing and a stronger one for treating growth hormone deficiency, all from the same core scaffold.
Is GHRP-2's survival through nasal tissue mainly explained by its unusual mirror-image amino acids?
If confirmed, this would be a design blueprint for making other peptide medicines that could be administered as a nasal spray rather than an injection. Needle-free growth hormone testing or treatment would be far easier for children and patients who need frequent dosing.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.7850325703620911 | openfold3-mlx |
| ranking score | 0.8390311002731323 | openfold3-mlx |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.656 | global PDE — lower = better |
| disorder | 0.121 | fraction disordered |
| chain pair ipTM (A, B) | 0.785 | interface quality |
▸3-letter notation
▸recipeopenfold3-mlx 0.3.1
| parameter | value |
|---|---|
| model | openfold3-mlx 0.3.1 |
| weights | — |
| hardware | — |
| mlx version | — |
| python | — |
| random seed | — |
| msa strategy | — |
| diffusion samples | 1 |
| runtime | 229s |
| predicted by | mlx@peptide |
| predicted at | 2026-05-03 |
▸citationbibtex
@peptide{pep10827,
sequence = {HAWFK},
target = {ghsr},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}