Hexarelin

Hexarelin (examorelin) is a synthetic hexapeptide GH secretagogue and the most potent GHS-R1a agonist in its structural class. It was developed by Europeptides in the 1990s as an optimized analog of GHRP-6, incorporating a 2-methyl-tryptophan (D-2-MeTrp) at position 2 to enhance receptor binding affinity and metabolic stability. Despite its potency, hexarelin has no regulatory approval and is classified as a research compound.

Hexarelin occupies a unique position among GHRPs: it has the highest absolute GH release potency in humans, verified in dose-response trials, while simultaneously demonstrating GH-independent cardioprotective effects via CD36 receptor activation on cardiomyocytes. This dual mechanism — GHS-R1a stimulation for GH release and CD36 for cardiac protection — makes hexarelin a pharmacologically distinctive research tool.

Hexarelin is a potent GHS-R1a agonist (ED50 approximately 0.5–0.64 mcg/kg). The 2-methyl substitution on D-Trp at position 2 provides approximately 3-fold greater GHS-R1a binding affinity than GHRP-6. Like GHRP-6, hexarelin activates Gαq/11 → PLC → IP3/DAG → Ca²⁺ release → GH exocytosis, with concurrent ACTH and prolactin co-stimulation.

The CD36-mediated cardioprotective mechanism is distinct from GHS-R1a signaling. Hexarelin binds CD36 (scavenger receptor class B, member 3) on cardiomyocytes, activating downstream signaling that: - Protects against ischemia-reperfusion injury - Reduces cardiomyocyte apoptosis (Bcl-2/Bax modulation) - Attenuates pro-inflammatory cytokine release (IL-1β, TNF-α) - Improves cardiac function independent of GH-mediated effects

This CD36 mechanism is also found in GHRP-6 and ghrelin, but hexarelin's superior metabolic stability makes it the preferred CD36 pharmacological tool in cardiac research.