GHRP-2 5mg Peptide

GHRP-2 is a synthetic hexapeptide, D-Ala-D-2-Nal-Ala-Trp-D-Phe-Lys-NH2, from the series of growth hormone secretagogues developed in Cyril Bowers' laboratory at Tulane University. Its International Nonproprietary Name is pralmorelin, and it also appears in the literature under the development codes KP-102 and GPA-748. The free base carries CAS 158861-67-7, molecular formula C45H55N9O6 and an average mass of 818.0 g/mol.

The peptide is an agonist at GHS-R1a, the growth hormone secretagogue receptor cloned from pituitary and hypothalamus by Howard and colleagues at Merck in 1996. That cloning came three years before the receptor's natural ligand was known: Kojima and colleagues purified ghrelin, a 28 amino acid octanoylated peptide, from rat stomach in 1999. GHRP-2 is therefore one of the compounds whose pharmacology led to the discovery of an entire endocrine axis rather than the other way round.

One fact separates GHRP-2 from every other peptide in this class. It is the only growth hormone secretagogue that has ever held a regulatory registration anywhere. In Japan it is registered as pralmorelin hydrochloride, used as a single intravenous provocative test for growth hormone deficiency. In every other jurisdiction it remains an unapproved compound supplied for laboratory research.

GHS-R1a is a Gq/11-coupled G protein coupled receptor expressed on pituitary somatotrophs and on neurons of the arcuate and ventromedial hypothalamus. Agonist occupancy activates phospholipase C, generates inositol trisphosphate, and mobilises intracellular calcium, which drives exocytosis of stored growth hormone. The receptor is notable among GPCRs for substantial constitutive signalling in the absence of any ligand, so a synthetic agonist acts on a system already running at a set point rather than switching a silent receptor on.

Bowers described the GHRP class as acting through a dual and complementary action on hypothalamus and pituitary, and a natural experiment in humans has since quantified how much of the effect belongs to each site. Gondo and colleagues compared 11 individuals with isolated growth hormone deficiency caused by a homozygous mutation of the GHRH receptor gene against 8 unrelated controls. GHRP-2 still raised serum GH 4.5-fold above baseline in the mutant group, from 0.11 to 0.49 micrograms per litre, which proves a receptor action directly on the somatotroph. In the controls the same stimulus produced a 79-fold rise, from 0.59 to 46.8 micrograms per litre. Most of the amplitude of a GHRP-2 response therefore depends on an intact GHRH signal, which is the pharmacological reason a GHRP and a GHRH analogue given together are synergistic rather than merely additive.

The GH pulse GHRP-2 produces is fast. In the Japanese validation study of 135 subjects, serum GH peaked within 60 minutes of a 100 microgram intravenous injection in every single participant, and typically within 15 to 30 minutes. Because the compound triggers release of stored hormone through a physiological pathway, negative feedback from IGF-I and somatostatin remains in circuit, which is the mechanistic contrast with exogenous recombinant GH.

GHS-R1a is not confined to somatotrophs, and this is the part of GHRP-2 pharmacology that matters most for anyone comparing it with ipamorelin. Raun and colleagues, testing five secretagogues head to head in conscious swine, found that GHRP-2 and GHRP-6 both raised plasma ACTH and cortisol, while ipamorelin did not at doses more than 200-fold above its own ED50 for GH release. Kimura and colleagues later demonstrated the corticotroph action directly in humans.

The compound came out of a chemistry programme at Tulane University led by Cyril Bowers, working with Polygen in Germany, that produced a series of small peptides of three to five residues and partial peptides suitable for subcutaneous, buccal, oral and depot delivery. Kaken Pharmaceutical acquired worldwide manufacturing and marketing rights and sublicensed North America to Wyeth. Development in the United States, aimed at growth hormone deficiency, was discontinued. Kaken carried its own programme through, developing KP-102D as a diagnostic agent for hypothalamo-pituitary function and KP-102LN, which reached Phase 2 in Japan for pituitary dwarfism. Japan is the only jurisdiction where any registration was granted.

The validation behind it is worth reading in detail, because it is the single best-controlled dataset on GHRP-2 in humans. Chihara and the KP-102 Study Group enrolled 77 healthy subjects and 58 patients whose peak GH on insulin tolerance testing was below 3 micrograms per litre. After an overnight fast, each received 100 micrograms of GHRP-2 intravenously, with blood drawn over the following two hours and GH measured by immunoradiometric assay. Serum GH peaked within 60 minutes in every subject. Peak concentrations were 84.6 plus or minus 60.9 micrograms per litre in the healthy group against 1.36 plus or minus 2.60 in patients, with no difference between hypothalamic and pituitary causes.

Two different cutoff numbers circulate for this test, and both are correct. The receiver operating characteristic crossing point ran from 15 to 20 micrograms per litre, and a 15 micrograms per litre threshold for peak GH corresponded to the 3 micrograms per litre diagnostic value used with the insulin tolerance test. The same paper reports the equivalent figure as 9 micrograms per litre when GH is calibrated against the recombinant World Health Organization 98/574 standard, and 9 micrograms per litre is the number quoted in Japanese practice for severe adult growth hormone deficiency. The two figures differ by assay calibration, not by protocol. Pages that quote one without the other, or that present them as competing claims, have lost the distinction.

The clinical argument for the test is that the insulin tolerance test, the international first-line standard, is contraindicated in patients with seizure disorders or ischaemic heart disease because it deliberately induces hypoglycaemia. A single provocative injection that produces a reproducible response, only mildly influenced by age and adiposity, gives an alternative in exactly those patients.

The most useful comparison in this family comes from a single Novo Nordisk study that tested the compounds against each other rather than assembling numbers from separate papers. In conscious swine, ipamorelin released GH with an ED50 of 2.3 plus or minus 0.03 nmol/kg and a maximum of 65 plus or minus 0.2 ng/mL, closely matching GHRP-6 at 3.9 plus or minus 1.4 nmol/kg and 74 plus or minus 7 ng/mL. GHRP-2 sat apart on both axes: more potent at an ED50 of 0.6 nmol/kg, but lower in maximal effect at 56 plus or minus 6 ng/mL. Anyone describing GHRP-2 as simply stronger is collapsing two separate properties into one word.

Ipamorelin is structurally the odd one out. It is a pentapeptide, Aib-His-D-2-Nal-D-Phe-Lys-NH2, identified within a series that deliberately removed the central Ala-Trp dipeptide of GHRP-1. GHRP-2 and GHRP-6 both retain a Trp in the core and both are hexapeptides. In the same swine experiment none of the secretagogues moved FSH, LH, prolactin or TSH, but GHRP-2 and GHRP-6 both raised ACTH and cortisol while ipamorelin did not, even more than 200-fold above its GH ED50. That result is the entire reason ipamorelin exists as a separate compound.

Hexarelin, the other hexapeptide in this catalogue, sits at the far end of the same axis. In 7 healthy volunteers given four 50 microgram doses through the night, hexarelin raised GH and prolactin across the whole night and ACTH and cortisol during the first half, while stage 4 sleep in the first half of the night and EEG delta power across the total night both fell significantly. In a separate study in 6 young adults, hexarelin at 1.0 and 2.0 micrograms per kilogram intravenously produced dose-dependent increases in GH, prolactin, ACTH and cortisol.

The practical reading of this family is that it sorts by selectivity, not by potency. GHRP-6 is the appetite-forward member with the weakest registration history. GHRP-2 is the more potent secretagogue with a real clinical dataset behind it and a documented corticotroph effect. Hexarelin is the most aggressive on GH and the most disruptive to the adrenal axis and to sleep architecture. Ipamorelin is the least potent per unit and the only one with GH selectivity comparable to GHRH itself.

This is the property most often described in vague terms and most rarely sourced. What is actually documented is this. In conscious swine, administration of both GHRP-6 and GHRP-2 resulted in increased plasma levels of ACTH and cortisol, in the same experiment where ipamorelin did not. That is the animal evidence, and it is a direct comparison rather than a cross-study inference.

The human evidence is more specific and more interesting. Kimura and colleagues studied 6 patients with various hypothalamo-pituitary disorders using three provocative tests. None of the 6 showed any significant ACTH or cortisol response to insulin-induced hypoglycaemia, yet significant ACTH release was observed during both the corticotropin-releasing hormone test and the GHRP-2 test. The authors read this as evidence that GHRP-2 stimulates ACTH secretion directly, rather than through the hypothalamic route that hypoglycaemia uses. In a group whose hypothalamic drive is broken, GHRP-2 still reaches the corticotroph.

The effect is real but it is not unbounded. In the GHRH-receptor-mutation study, basal and post-GHRP-2 serum levels of ACTH, cortisol and prolactin were similar between the deficient group and controls, and TSH did not change in either group after GHRP-2. So the compound engages the corticotroph without producing a runaway adrenal response, and it leaves the thyroid axis alone.

Retail information pages routinely attach a percentage to this, describing cortisol as rising by some fixed proportion or as some fixed fraction of the GHRP-6 response. No published trial supports a number of that form. What can be said with a citation is that GHRP-2 has demonstrable direct ACTH-releasing activity in humans, that it shares this property with GHRP-6 and hexarelin, and that ipamorelin is the member of the family in which the property has been specifically shown to be absent.

The appetite effect has been measured properly, which is rare for a compound in this category. Laferrere, Hart and Bowers ran a double-blind randomised crossover in 19 healthy, weight-stable subjects, 10 lean and 9 obese, each attending three visits. Each visit delivered a 270 minute subcutaneous infusion of GHRP-2 at 1 microgram per kilogram per hour, at 0.1 microgram per kilogram per hour, or placebo. Hunger and fullness were rated on visual analogue scales around a fixed 320 kcal breakfast, and the endpoint was ad libitum intake at a buffet lunch at 240 minutes.

Intake rose in a clearly dose-dependent way: 10.2 plus or minus 3.9 percent above placebo at the low rate and 33.5 plus or minus 5.8 percent at the high rate. Obesity status did not influence the effect, and serum GH rose dose-dependently in all subjects. Appetite ratings before the meal were higher on the high rate while post-meal fullness was unchanged, so the effect acts on drive to eat rather than on satiation.

Whether that translates over months is a separate question, and it has been asked. Mericq and colleagues gave oral GHRP-2 at 900 micrograms per kilogram twice daily for 12 months to 10 prepubertal children with growth hormone deficiency. Seven of the 10 reported a significant increase in appetite, but only during the first 6 months. BMI standard deviation score moved from 0.21 plus or minus 1.5 to 0.25 plus or minus 1.5, which did not reach statistical significance. The appetite signal is real, dose-dependent, and appears to attenuate rather than compound.

The widely repeated claim that GHRP-2 is meaningfully less orexigenic than GHRP-6 deserves a caveat. No head-to-head human appetite trial between the two has been published. The claim rests on the potency difference, on the fact that GHRP-6 was characterised early as a strong stimulus to food intake, and on accumulated clinical impression. It is a reasonable inference, not a measured result, and this record does not present it as one.

Johansen and colleagues compared five peptidyl secretagogues in the male rat across several routes. After intravenous bolus, plasma concentrations of every peptide declined biexponentially. The routes separated the compounds sharply. Ipamorelin showed a systemic plasma clearance five-fold lower than GHRP-6 and was excreted mainly in urine, whereas GHRP-6 went predominantly into bile. On the nasal route, bioavailability was estimated at roughly 50 percent for GHRP-2, roughly 20 percent for ipamorelin, and lower for GHRP-6, which is why GHRP-2 was the member of the series taken forward into an intranasal formulation.

That formulation was tested clinically. Pihoker and colleagues evaluated 24 children of short stature with at least one conventional provocative agent alongside intravenous GHRH and intravenous GHRP-2. GHRH and GHRP-2 gave similar responses in each child and both predicted pituitary reserve better than arginine, L-dopa with exercise, or insulin. Twelve children given GHRH and GHRP-2 simultaneously showed a synergistic GH response. Fifteen children received intranasal GHRP-2 across a 5 to 20 micrograms per kilogram range; all 15 responded, with mean peak GH of 31.3 micrograms per litre at 15 micrograms per kilogram, and the intranasal preparation was well tolerated.

The half-life figures circulating for GHRP-2 span an order of magnitude, from 15 minutes to 2 hours, because two different quantities are being conflated. Plasma elimination is rapid, and no published human study reports a terminal half-life approaching an hour. The GH pulse is a separate curve: serum GH peaked within 60 minutes in every subject of the Japanese validation study. Assay detectability is a third curve again. An anti-doping method validated on dried blood spots detected GHRP-2 up to 4 hours after a single 100 microgram intravenous dose at a limit of detection of 50 pg/mL, with venous spots reading higher than capillary spots. Detectable at 4 hours is not the same as active at 4 hours.

The short residence time is treated in the literature as the limiting property of the molecule rather than a feature. A mono-PEGylated GHRP-2, synthesised using mPEG-NHS ester at a 0.8 to 1 molar ratio in anhydrous aprotic solvent and characterised by MALDI-TOF, showed more stable activity in rats than the parent peptide, indicating that the biological activity survives conjugation while the plasma half-life extends.

Claims about GHRP-2 tolerance are contradictory across the open web, with some sources asserting maintained response on repeat administration and others prescribing cycling to preserve receptor sensitivity. Neither position is usually sourced, so it is worth separating what has been observed from what has been assumed.

The longest continuous exposure with hormonal endpoints is the critical illness study. Thirty-three men with prolonged critical illness received a 5-day continuous GHRP-2 infusion at 1 microgram per kilogram per hour, alone or combined with TRH, or with TRH and pulsatile GnRH. GH, TSH and LH secretion were quantified by deconvolution analysis of 20-minute sampling from 2100 to 0600 at baseline and on nights 1 and 5. GHRP-2 infusion reactivated GH secretion and normalised serum IGF-I, IGFBP-3 and the acid-labile subunit, all of which had been significantly suppressed. The axis did not collapse across five days of uninterrupted agonism. The same study noted that on day 5 serum lactate and white blood cell count were increased by GHRP-2 infused alone and in combination with TRH, but not when GnRH pulses were added.

The longest exposure of any kind is the paediatric oral study, 12 months of twice-daily oral GHRP-2 in 10 children, which continued to show a transient appetite effect and no significant BMI change but was not designed to quantify GH response decay over that period.

What does not exist is a controlled human study establishing chronic GHS-R1a downregulation with GHRP-2 specifically. The pronounced desensitisation frequently attributed to this compound is documented for hexarelin, a different hexapeptide with a different receptor engagement profile, and the transfer of that finding to GHRP-2 is an assumption. The Japanese registration compounds the gap: a single-injection provocative test generates no repeat-administration data at all, so the best-controlled dataset on the molecule is structurally silent on the question people most often ask about it.

GHRP-2 has a documented adulteration problem, which makes independent identity confirmation more than a formality. Poplawska and Blazewicz analysed a seized injection vial by liquid chromatography coupled to high-resolution quadrupole time-of-flight tandem mass spectrometry and identified, by de novo sequencing, a novel heptapeptide of molecular weight 874.02 Da: a glycine analogue of GHRP-2, apparently synthesised to sit outside existing doping detection methods. That analogue is 56 Da heavier than GHRP-2. Anything relying on approximate mass alone would not distinguish them.

Several molecular facts are consistently reported incorrectly in secondary sources. The correct free-base formula is C45H55N9O6; the variant C45H54N9O6 that circulates in some chemical databases is charge-unbalanced and wrong. The C-terminal amide is part of the molecule, so a sequence written to a free acid lysine describes a different compound with a different mass. The designation SK&F 110679 belongs to GHRP-6, not GHRP-2, and appears misattributed on a number of information pages.

Salt form matters for anyone reconciling a label mass against a certificate of analysis. Research-grade material is commonly supplied as an acetate, while the product registered in Japan is pralmorelin hydrochloride, C45H57Cl2N9O6, with a formula weight of 890.9 g/mol against 818.0 for the free base. Peptide content per milligram of salt therefore differs by roughly 8 percent between those two forms alone. A certificate of analysis that states purity but not salt form and peptide content has not stated enough to convert mass into moles.

For analytical work, LC-MS/MS methods for GHRP-2 are well established through anti-doping research. A validated dried blood spot procedure reached a limit of detection of 50 pg/mL for the parent peptide, and long-term stability in that dry matrix was confirmed beyond two years. The principal metabolite, AA-3, was present at levels too low in dried blood spots to support its own determination, so parent-compound detection remains the practical target.