What Has Published Research Reported About GHRP-2?

What is GHRP-2?

GHRP-2 is a synthetic six-residue peptide in the family of growth hormone releasing peptides, or GHRPs, small synthetic molecules that stimulate growth hormone (GH) release from the pituitary. It is also called pralmorelin and, in the Japanese pharmacology literature, KP-102. A 2004 paper by Doi and colleagues uses KP-102 and GHRP-2 as names for the same compound and gives its chemical name as D-alanyl-3-(2-naphthyl)-D-alanyl-L-alanyl-L-tryptophyl-D-phenylalanyl-L-lysinamide (source 3). In short form the sequence is D-Ala-D-2-Nal-Ala-Trp-D-Phe-Lys-NH2, where 2-Nal is 2-naphthylalanine and the C-terminus is amidated.

Comparing the written sequences, GHRP-2 shares its last four residues, Ala-Trp-D-Phe-Lys-NH2, with GHRP-6, the hexapeptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 described by Bowers, Momany, Reynolds and Hong in Endocrinology in 1984 (source 1). The first two positions differ: GHRP-2 carries D-Ala and D-2-Nal where GHRP-6 carries His and D-Trp. Working from the sequence, the free peptide comes out as C45H55N9O6, about 818.0 daltons on average or 817.43 daltons monoisotopic. These are calculated values rather than figures quoted from a cited paper, and they matter for laboratories, as discussed below.

This Steadfast Research Group profile summarizes what the primary literature reported about GHRP-2, from cell and animal pharmacology to human studies and analytical work. It is written for researchers reading that record and covers published observations only.

How was GHRP-2 first characterized in cells and animals?

A 1994 report in the Journal of Endocrinology used a perifusion system with primary cultured ovine anterior pituitary cells (source 2). The abstract reported that the GH release produced by the highest concentration tested, 100 nM KP 102, was completely blocked by [Ac-Tyr1, D-Arg2]GRF(1-29), a compound regarded as a specific GH-releasing factor (GRF) receptor antagonist, and that blocking calcium channels with cadmium also removed the GH increase. The same abstract reported no cross-desensitization between KP 102 and GRF responses (source 2).

The fuller pharmacology came from Kaken Pharmaceutical’s laboratories in a 2004 paper in Arzneimittel-Forschung (source 3). In conscious rats, the authors reported that KP-102 released more GH than injected GHRH, while under pentobarbital anesthesia the two were roughly equal in potency. In conscious dogs, KP-102 raised serum GH where GHRH had no effect. In cultured rat pituitary cells it stimulated GH, but less strongly than GHRH did (source 3).

Two lesion experiments in the same paper bear on site of action. The GH response was absent in hypophysectomized rats, which have no pituitary, but still present in rats with median eminence lesions (source 3). The paper also reported that KP-102 increased ACTH and corticosterone in conscious rats but not prolactin (source 3). The Steadfast Research Group profile of ipamorelin covers a later comparison of GHRPs on exactly this selectivity question.

Which receptor does GHRP-2 act on?

GHRP-2 was characterized before its receptor was known. In 1996, Howard and colleagues reported in Science the cloning of a G protein-coupled receptor in the pituitary and hypothalamus that functioned in GH release and served as the target of synthetic growth hormone secretagogues (source 4). Three years later, Kojima and colleagues reported in Nature the purification of ghrelin, a 28-residue acylated peptide from rat stomach that bound this receptor and released GH (source 5).

The 1994 ovine-cell paper predates both reports, which is why it frames its question around GRF receptor pharmacology rather than the secretagogue receptor (source 2). Bowers, a co-author of the 1984 GHRP-6 paper (source 1), later titled a 2001 commentary in the Journal of Clinical Endocrinology & Metabolism “Unnatural growth hormone-releasing peptide begets natural ghrelin” (source 6). By 2005, investigators studying human eating behavior were describing GHRP-2 as a tool for investigating ghrelin effects (source 9).

Growth hormone releasing peptide (GHRP)

A small synthetic peptide that stimulates GH release from the pituitary. GHRP-6, described in 1984, is the best-known early member (source 1).

KP-102 and pralmorelin

Alternative names for GHRP-2 used in the Japanese pharmacology literature (source 3).

GHRH (GRF)

Growth hormone-releasing hormone, the hypothalamic peptide that normally drives GH secretion; used as a comparator in the GHRP-2 studies (sources 2, 3 and 7).

Growth hormone secretagogue receptor

The G protein-coupled receptor cloned in 1996 as the target of synthetic GH secretagogues and later shown to bind ghrelin (sources 4 and 5).

Hypophysectomy

Surgical removal of the pituitary, used in the 2004 rat work to test whether a response required the gland (source 3).

What did early human studies report about GHRP-2?

A 1997 study in Peptides by Arvat, di Vito, Maccagno and colleagues compared GHRP-2 with hexarelin in healthy young adults (source 7). The two peptides produced a similar, strong GH response that was higher than the response to GHRH (p < 0.05). The same study measured prolactin, ACTH and cortisol and compared those responses with reference stimuli, TRH for prolactin and human corticotropin-releasing hormone for ACTH and cortisol (source 7). Together with the rat data, this places GHRP-2 among the older GHRPs that were measured against the pituitary-adrenal axis as well as GH. The Steadfast Research Group profile of hexarelin covers the other peptide in that comparison.

How was GHRP-2 evaluated as a diagnostic stimulus?

The largest human study in this record was published in 2007 in the European Journal of Endocrinology by Chihara and colleagues (source 8). It enrolled 77 healthy subjects and 58 participants whose peak GH had been below 3 µg/L on the insulin tolerance test, the standard comparator. After an overnight fast, each participant received GHRP-2 intravenously and GH was measured over the following two hours (source 8).

The separation between groups was wide. Peak GH averaged 1.36 ± 2.60 µg/L in the GH-deficient group and 84.6 ± 60.9 µg/L in the healthy group, with no difference between hypothalamic and pituitary causes of deficiency (source 8). The authors concluded that severe GH deficiency could be identified with a peak GH cut-off of 15 µg/L, or 9 µg/L when GH was calibrated against the WHO 98/574 standard. They described the test as reproducible and only mildly affected by age and adiposity, and the adverse reactions they recorded, flushing, borborygmus and a rise in white blood cell count, were transient (source 8). The two cut-offs for one test show how much a GH assay calibration can change a published threshold.

Did GHRP-2 change food intake in research subjects?

In 2005, Laferrère, Abraham, Russell and Bowers reported in the Journal of Clinical Endocrinology & Metabolism a study of healthy men given a GHRP-2 infusion or saline (source 9). The men ate 35.9 ± 10.9 percent more food after the GHRP-2 infusion than after saline, and the macronutrient composition of the food eaten did not differ between conditions. The authors proposed GHRP-2 as a tool for investigating ghrelin effects on eating behavior (source 9). The paper’s title compared the effect with that of ghrelin, the natural ligand of the secretagogue receptor (sources 5 and 9).

How do laboratories identify GHRP-2?

Two 2010 analytical papers came from an anti-doping context, in which GHRP-2 appears on the World Anti-Doping Agency prohibited list as a releasing factor for GH (source 11). Okano and colleagues described a liquid chromatography tandem mass spectrometry method for urinary GHRP-2 and its metabolite AA-3, D-Ala-D-(β-naphthyl)-Ala-Ala-OH. Recoveries ran from 84 to 101 percent, and in ten male volunteers given GHRP-2 intravenously, both the unchanged peptide and AA-3 were detected in urine in every case (source 10).

Also in 2010, Thomas and colleagues reported identifying GHRP-2 in a commercial tablet product using high-resolution, high-accuracy mass spectrometry, relying on accurate masses and fragment ion ratios after extraction from the tablet matrix (source 11). For a research laboratory the lesson is about identity. GHRP-2 at about 818.0 daltons calculated sits about 55 daltons below GHRP-6 at 873.0 and about 69 daltons below hexarelin at 887.1, gaps that mass spectrometry resolves easily. Confirming the expected mass and checking purity by HPLC against a batch-matched Certificate of Analysis are the routine ways to tell closely related GHRPs apart.

What remains unresolved in the GHRP-2 literature?

The record has clear limits. The 2004 pharmacology paper came from Kaken Pharmaceutical’s Central Research Laboratories, and several papers share investigators, including Bowers on the 1984, 2001 and 2005 papers (sources 1, 6 and 9). Within the sources reviewed here, most findings rest on a single study each rather than on independent replications.

Interpretation is also complicated by the order of discovery. The 1994 cell experiments pointed to a GRF-linked pathway while also showing no cross-desensitization (source 2), and the receptor and ghrelin findings that later organized the field arrived in 1996 and 1999 (sources 4 and 5). The diagnostic data show that a single published threshold depends on assay calibration (source 8). The food intake result came from one study in healthy men (source 9), and no source reviewed here followed it with longer observation periods for GHRP-2.