The History of the Discovery of GHRP-6

GHRP-6 is the first well-characterized synthetic peptide capable of specifically stimulating the release of growth hormone. Its history is an example of how a persistent search for a "drug without a target" changed endocrinology: from this hexapeptide grew entire programs of pharmaceutical companies, the discovery of a new receptor, and the hormone ghrelin. The editorial team tells how GHRP-6 appeared and why it is still mentioned in physiology textbooks.

The scientific background: the puzzle of growth hormone regulation

By the 1970s endocrinologists already knew that growth hormone secretion is controlled by the hypothalamus. The inhibitory hormone - somatostatin, isolated in 1973 - was known. But the stimulating hypothalamic hormone, somatoliberin (GHRH), still could not be identified: its structure was established only in 1982, while studying pancreatic tumors of patients with acromegaly.

During this period several laboratories were searching for synthetic substances that could stimulate the pituitary. Cyril Bowers of Tulane University in the USA drew attention to synthetic analogs of enkephalins - small opioid peptides. Some of them, stripped of opioid action, showed a weak ability to release growth hormone from pituitary cells.

This was unexpected: neither enkephalins nor their receptors explained such an effect. Bowers hypothesized that a separate mechanism of pituitary stimulation exists, and decided to purposefully enhance the activity of the molecules he had found.

Such a strategy had risks. The researchers worked "blind": without knowing the receptor and the natural ligand, they could rely only on biological tests and chemical intuition. Yet it was precisely this work that led to GHRP-6.

Designing the molecule: chemistry and computer modeling

Bowers's key partner became the theoretical chemist Frank Momany, who was engaged in the conformational analysis of peptides. He used computer calculations of the energetically favorable spatial forms of molecules to predict which amino acid substitutions could enhance activity. For the early 1980s this was a cutting-edge approach.

In 1981, in the journal Endocrinology, the group published a paper on the design and synthesis of a series of growth-hormone-releasing peptides. Among them stood out a hexapeptide with the structure His-D-Trp-Ala-Trp-D-Phe-Lys-NH2, which later received the name GHRP-6.

A distinctive feature of GHRP-6 is the presence of D-amino acids, mirror forms of ordinary amino acids. They make the peptide more resistant to enzymes and fix the required spatial form. It was precisely this conformation, as it turned out later, that matched the requirements of a receptor whose existence was not yet known at the time.

In 1984 Bowers, Momany, Reynolds, and Hong described the in vitro and in vivo activity of GHRP-6 in a paper now considered a classic. They showed that the peptide acts directly on the pituitary, specifically stimulates growth hormone, and does not substantially affect most other hormones in the models used.

From rats to humans: the first clinical data

After the activity in animals was described, the question arose whether GHRP-6 would work in humans. In the late 1980s Bowers and colleagues conducted a study in healthy men and demonstrated that intravenous administration of GHRP-6 causes a marked dose-dependent rise in growth hormone.

The most important discovery was the synergy with somatoliberin. Simultaneous administration of GHRP-6 and GHRH caused a release of growth hormone much greater than the sum of the effects of each substance separately. This became convincing proof that GHRP-6 acts not through the GHRH receptor but through a different, independent mechanism.

Further studies showed other effects of GHRP-6 as well: increases in prolactin, ACTH, and cortisol, as well as stimulation of appetite. Frieboes and co-authors (1995) described that GHRP-6 changes sleep architecture and raises the levels of stress-axis hormones in healthy men.

It was also noted that with age the response to GHRP-6 declines, but is preserved better than the response to GHRH. This gave rise to interest in secretagogues as a possible means of correcting the age-related decline in growth hormone - an interest that later proved to be greatly exaggerated.

GHRP-6 as a template for new drugs

A drawback of GHRP-6 as a potential drug was its peptide nature: it was poorly absorbed when taken orally and was quickly broken down. Pharmaceutical companies, in particular Merck, decided to use it as a "template" for the search for non-peptide molecules with the same action.

In 1993 Roy Smith's group published in Science a description of the non-peptide secretagogue L-692,429, and later the oral ibutamoren (MK-677) appeared. These molecules were structurally not at all similar to GHRP-6 but acted through the same mechanism.

• 1981-1984:design and biological characterization of GHRP-6.
• Late 1980s:the first human studies and the discovery of synergy with GHRH.
• Early 1990s:second-generation peptides - GHRP-1, GHRP-2, hexarelin.
• 1993:the first non-peptide secretagogue L-692,429.
• 1996:cloning of the GHS-R receptor (Howard et al., Science).
• 1999:discovery of the natural ligand - ghrelin (Kojima et al., Nature).

Cloning the receptor became possible precisely thanks to synthetic secretagogues: labeled molecules made it possible to find the protein they bind to. And the search for the natural ligand ended with the discovery of ghrelin - a stomach hormone that stimulates both the release of growth hormone and appetite.

Thus GHRP-6 effectively became a "key" created before the "lock" and the body's "original key" were found.

The legacy of GHRP-6 today

GHRP-6 never became a registered medicinal product. Its clinical potential was limited by the short duration of action, the need for injections, stimulation of appetite and cortisol, and the appearance of more potent and convenient analogs.

In science, however, it remains an important tool. GHRP-6 is used as a reference agonist of the ghrelin receptor in experimental work, and its possible effects beyond the growth hormone axis are also being studied - for example, in models of tissue damage. These studies are mostly preclinical, and it is premature to transfer their results to humans.

Outside scientific laboratories, GHRP-6 is distributed on the gray market as a "research peptide." Such products do not undergo pharmaceutical control, and their composition and sterility are not guaranteed.

For athletes GHRP-6 is a prohibited substance: it belongs to section S2 of the WADA Prohibited List along with other growth-hormone-releasing peptides and is prohibited at all times.

Editorial conclusions

GHRP-6 emerged as the result of a purposeful chemical search that combined peptide synthesis and computer modeling. It became the first well-described synthetic stimulator of growth hormone secretion with a mechanism independent of GHRH.

The discovery of synergy with somatoliberin and the development of non-peptide analogs based on it led to the cloning of the GHS-R receptor and the discovery of ghrelin.

Despite its scientific value, GHRP-6 has no medical indications, and its use outside research is associated with unknown product quality and violation of anti-doping rules.

We also recommend reading our materials on the history of the discovery of GHRP-2, on GHRP-6 and cancer risks, and on the effect of GHRP-2 on sleep.

References

1. Momany FA, Bowers CY, Reynolds GA, et al. Design, synthesis, and biological activity of peptides which release growth hormone in vitro. Endocrinology. 1981;108(1):31–39.
2. Bowers CY, Momany FA, Reynolds GA, Hong A. On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology. 1984;114(5):1537–1545.
3. Bowers CY. Growth hormone-releasing peptide (GHRP). Cell Mol Life Sci. 1998;54(12):1316–1329.
4. Smith RG, Cheng K, Schoen WR, et al. A nonpeptidyl growth hormone secretagogue. Science. 1993;260(5114):1640–1643.
5. Howard AD, Feighner SD, Cully DF, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996;273(5277):974–977.
6. Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656–660.
7. Frieboes RM, Murck H, Maier P, et al. Growth hormone-releasing peptide-6 stimulates sleep, growth hormone, ACTH and cortisol release in normal man. Neuroendocrinology. 1995;61(5):584–589.
8. Smith RG, Van der Ploeg LH, Howard AD, et al. Peptidomimetic regulation of growth hormone secretion. Endocr Rev. 1997;18(5):621–645.