GHRP-2 Research Peptide

GHRP-2 is one of very few ghrelin-receptor agonists to become a licensed product. As pralmorelin dihydrochloride, it is approved in Japan as a diagnostic agent and sold by Kaken Pharmaceutical under the name GHRP Kaken 100. Its role is narrow: to show whether the pituitary can still release growth hormone when challenged, a question that arises when adult growth-hormone deficiency is suspected. That approval belongs to the Japanese medicine and its diagnostic use; research-grade GHRP-2 is a separate product with no licensed role.

Why was a new test wanted? The international reference method, the insulin tolerance test, works by deliberately lowering blood sugar, which rules it out for some patients. A Japanese multicentre team, the KP-102 Study Group led by Chihara, set GHRP-2 against it in 77 healthy adults and 58 patients whose insulin test had already shown a very low growth-hormone peak. In every participant the peak arrived within an hour. Healthy volunteers averaged around 85 µg/L at the top of the curve, while the patients averaged under 1.4 µg/L, with no gap between hypothalamic and pituitary causes. Repeat tests gave consistent readings.

Line the two sequences up and the family likeness is plain. GHRP-6 reads His-D-Trp-Ala-Trp-D-Phe-Lys-NH2; GHRP-2 keeps its last four residues untouched and edits only the first two. The opening histidine becomes D-alanine, and the D-tryptophan in second place becomes D-2-naphthylalanine, usually shortened to D-2-Nal. Naphthylalanine is absent from natural proteins. Its side chain is naphthalene, two benzene rings fused edge to edge, so it is flatter and more water-repelling than the indole of tryptophan and contains no nitrogen.

Those edits paid off. Cyril Bowers, whose Tulane laboratory built this peptide family, reported that GHRP-6, the seven-residue GHRP-1 and then GHRP-2 grew steadily more effective at releasing growth hormone, first in rats and then in human volunteers. Yet a Merck comparison in rat pituitary cells showed that the structural changes had not altered the target: maximal amounts of GHRP-2 and GHRP-6 given together released no more than either alone, and each peptide desensitised the cells to the other. With D-residues at positions one, two and five, the chain is also an awkward fit for many protein-cutting enzymes.

Growth hormone is the headline, but GHRP-2 does not send a perfectly clean signal. In Turin, Ezio Ghigo’s group gave GHRP-2 and its relative hexarelin to six healthy young adults and compared four hormones against reference stimuli. Both peptides produced a strong growth-hormone rise, larger than the response to GHRH itself. Prolactin increased as well, though by less than after TRH, the classic prolactin trigger. ACTH and cortisol climbed to levels comparable with those seen after corticotrophin-releasing hormone, the body’s main stress-axis messenger. A follow-up from the same group found matching prolactin, ACTH and cortisol rises for GHRP-2, hexarelin and an easily iodinated hexarelin analogue used in binding work.

The species makes a difference. In the KP-102 rat pharmacology programme, GHRP-2 raised ACTH and corticosterone, the main rodent stress steroid, yet left prolactin unchanged. The choice of model therefore shapes which secondary signals appear, and a panel covering prolactin and adrenal hormones alongside growth hormone gives a much fuller picture of a GHRP-2 experiment.

One of the more surprising settings for GHRP-2 research has been the intensive care unit. Greet Van den Berghe’s group in Leuven studied men with prolonged critical illness, a state in which the pulsed release of growth hormone, TSH and LH becomes heavily suppressed. Their hypothesis was that the pituitary in these patients is under-stimulated rather than worn out, and so might answer a releasing signal.

In a randomised study of 33 men, five days of GHRP-2 infusion restarted pulsatile growth-hormone secretion and returned IGF-I and its main binding-protein complex to normal levels. Adding TRH restored thyroid hormones within a day, and adding pulses of GnRH on top raised LH output and testosterone. Markers of protein breakdown, such as urea production, fell only in the combination groups and not with GHRP-2 on its own. The work is best read as a demonstration of how far a suppressed pituitary can be reawakened, with GHRP-2 serving as the probe.