In 1980 the first highly potent GH-Releasing peptide was developed and named GHRP-6. This peptide was found to illicit a strong GH release response and so became the first member of a class of growth hormone releasing peptides more broadly called GH secretagogues. Structurally GHRP-6 is composed of the amino acids L-Histidine, D-Tryptophan, L-Alanine, L-Tryptophan, D-Phenylalanine and L-Lysine. The “L” form of an amino acid is the naturally occurring form and often in the nomenclature the “L” is dropped. The “D” form does not occur in nature and is the isomeric form (i.e. mirror image) of the naturally occurring “L” form.
GHRP-6 is composed of both natural and isomeric forms of those aforementioned six amino acids. Its structure is represented as:
Investigators subsequently modified the structure of GHRP-6 and identified more potent peptides. For example, activity was enhanced by replacing D-Trp with D-2-(2-napthyl)alanine and His with D-Alanine to create GHRP-2 whose structure is represented as:
In 1982, after a long search the natural hormone “Growth Hormone Releasing Hormone” (GHRH) was finally isolated and identified. As a result the interest in Growth Hormone Secretagogues (at that point limited to the three peptides) faded. Eventually researchers discovered that those GH-Releasing Peptides (specifically GHRP-6 & GHRP-2) followed a mode of action which bound them to and was mediated through receptors different from those for GHRH. In addition researches discovered that these GH-Releasing Peptides acted synergistically with the natural hormone Growth Hormone Releasing Hormone (GHRH) in vivo (in both laboratory animals & humans) to produce large releases of Growth Hormone.
Taken together these two discoveries made it clear that GHRPs were not simply surrogates of GHRH. GHRP-6 and its analogues were artificial activators of a separate newly discovered receptor termed the “Growth Hormone Secretagogue Receptor” (GHS-R). Eventually the natural hormone Ghrelin was discovered as the endogenous ligand that binds to the GHS-R. Together the natural hormone Ghrelin, and all the synthetic compounds (both peptides & smaller molecules) such as GHRP-6 were termed “Growth Hormone Secretagogues” (GHSs).
This nomenclature continues in the literature to this day however increasingly new terminology is used. For instance the “Ghrelin Receptor” is synonymous with “GHS-R” and “Ghrelin mimetics” are synonymous with all the synthetic compounds that are capable of binding to the GHS-R. This paper uses the more established nomenclature throughout.