Hexarelin

Hexarelin (Examorelin) is a synthetic hexapeptide growth hormone secretagogue that activates the growth hormone secretagogue receptor (GHS-R1a), the same receptor targeted by the endogenous hormone ghrelin. It is structurally related to GHRP-6 but contains a 2-methyl modification on the D-Trp residue that confers greater GH-releasing potency and additional receptor selectivity.

Upon binding to GHS-R1a on anterior pituitary somatotrophs, Hexarelin triggers calcium influx through IP3-mediated intracellular signalling, stimulating the exocytosis of stored growth hormone granules. This mechanism is complementary to GHRH, which acts via cAMP, explaining why GHRP-class peptides and GHRH produce synergistic rather than additive GH release.

Distinctively, Hexarelin demonstrates significant cardioprotective properties that appear to be independent of its GH-releasing activity. It binds to the CD36 scavenger receptor on cardiac cells, activating downstream PPARgamma signalling and reducing oxidative stress in myocardial tissue. This cardiac tropism distinguishes Hexarelin from other GH secretagogues and has driven substantial research into its effects on cardiac remodelling, ischaemia-reperfusion injury, and heart failure. Like GHRP-6, Hexarelin produces modest increases in prolactin and cortisol, though it does not stimulate appetite as strongly due to its modified receptor binding profile.

Hexarelin was developed in the early 1990s by Romano Deghenghi and colleagues in Italy as part of a systematic effort to create more potent and selective analogues of the first-generation growth hormone secretagogue GHRP-6. The 2-methyltryptophan substitution in the D-Trp position was found to significantly increase GH-releasing potency.

Clinical studies in the mid-1990s confirmed Hexarelin as one of the most potent peptide GH secretagogues available, with robust GH release observed after subcutaneous, intranasal, and even oral administration. However, during clinical development, researchers discovered an unexpected and prominent cardioprotective effect. Studies showed that Hexarelin reduced infarct size, improved cardiac contractility, and attenuated ventricular remodelling after myocardial infarction, even at doses too low to significantly elevate GH levels. This cardiac tropism was traced to binding at the CD36 receptor, opening an entirely new research direction. The cardiac research programme has generated particular interest in post-infarction recovery and heart failure models.