GHRP-6

GHRP-6 (growth hormone releasing peptide-6) is the prototype synthetic GH secretagogue hexapeptide, discovered by Bowers et al. in the 1980s through systematic structure-activity optimization of enkephalin analogs. It was the founding member of a class of compounds that ultimately led to the discovery of the endogenous ghrelin system (ghrelin is the natural ligand for the GHS-R1a receptor that GHRP-6 activates).

GHRP-6 is a research compound with no approved therapeutic indication. Its primary research interest is in GH stimulation for growth hormone deficiency investigation and, separately, in GH-independent cytoprotective and anti-fibrotic effects via CD36 receptor activation. It is less selective than newer GHRPs (ipamorelin, GHRP-2) and produces more pronounced appetite stimulation and cortisol co-activation.

GHRP-6 binds GHS-R1a (the ghrelin receptor) with high affinity, activating Gαq/11 signaling to stimulate both GH release from pituitary somatotrophs and ghrelin-like orexigenic effects from hypothalamic neurons. At clinical GH-releasing doses, GHRP-6 also activates ACTH/cortisol and prolactin secretion, reducing its hormonal selectivity compared to ipamorelin.

A pharmacologically significant second mechanism operates through CD36 (scavenger receptor class B, member 3), a cell surface receptor expressed on cardiomyocytes, macrophages, and endothelial cells. CD36 activation mediates GHRP-6's cytoprotective, anti-inflammatory, and anti-fibrotic effects in cardiac and multi-organ injury models — effects that are independent of GH axis activation and cannot be explained by pituitary receptor pharmacology alone. The CD36 pathway engages STAT3, Bcl-2, and NF-κB signaling to suppress apoptosis and inflammatory cell infiltration.