Tag: Hexapeptide ghrelin receptor agonist

Hexarelin (examorelin; His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2; CAS 140703-51-1; molecular weight 887.04 g/mol) is a synthetic hexapeptide growth hormone secretagogue developed in the early 1990s by Romano Deghenghi and colleagues at Europeptides (subsequently Mediolanum Farmaceutici) as a chemically stabilized analog of growth hormone releasing peptide-6 (GHRP-6). The compound acts through two pharmacologically distinct receptor systems: the growth hormone secretagogue receptor type 1a (GHS-R1a), a G-protein-coupled receptor expressed predominantly in the hypothalamic-pituitary axis that mediates potent, dose-dependent growth hormone release; and CD36, a class B scavenger receptor expressed on cardiomyocytes, macrophages, and endothelial cells that mediates cardioprotective, anti-fibrotic, and anti-atherogenic effects independent of growth hormone secretion. The dual-receptor pharmacology distinguishes hexarelin from both the endogenous ligand ghrelin and from the more selective growth hormone secretagogue ipamorelin, and provides the molecular basis for a research literature that extends substantially beyond the neuroendocrine indication for which the compound was originally developed.

The growth hormone releasing activity of hexarelin was first characterized in humans by Ghigo, Arvat, and colleagues in 1994, who demonstrated dose-dependent GH release after intravenous, subcutaneous, intranasal, and oral administration in healthy volunteers, with subcutaneous bioavailability of approximately 77 percent, intranasal bioavailability of approximately 5 percent, and oral bioavailability of approximately 0.3 percent [1]. At an intravenous dose of 1 microgram per kilogram, hexarelin produced a GH response approximately twice that of equimolar growth hormone releasing hormone (GHRH), and co-administration with GHRH produced synergistic GH elevation described as “massive” even at low hexarelin doses [1, 2]. The compound reached Phase II clinical trials for the diagnosis and treatment of growth hormone deficiency and for congestive heart failure but was never marketed, principally owing to tachyphylaxis of the GH-releasing response on repeated daily dosing, with GH output declining by 50 to 80 percent within two to four weeks of continuous administration [3, 4].

The cardiovascular pharmacology of hexarelin represents the most pharmacologically distinctive aspect of the compound. Bhatt et al. (2002) and Bhargava et al. (2004) established that the cardioprotective effects of hexarelin in ischemia-reperfusion models are mediated through CD36 rather than GHS-R1a, using knockout mouse experiments that demonstrated abolition of cardioprotection in CD36-null animals while the effect was preserved in GHS-R1a-null animals [5, 6]. In isolated perfused rat hearts subjected to 30 minutes of ischemia followed by 120 minutes of reperfusion, hexarelin at 1 micromolar reduced infarct size by approximately 25 to 40 percent [7]. The CD36-mediated signaling involves activation of peroxisome proliferator-activated receptor gamma (PPARgamma), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) survival pathways, and suppression of pro-apoptotic caspase-3 activity [8, 9]. In spontaneously hypertensive rats, five weeks of hexarelin treatment significantly reduced cardiac fibrosis by decreasing interstitial and perivascular collagen deposition, reducing collagen I and III expression, and attenuating left ventricular hypertrophy [10]. Human clinical studies have demonstrated acute positive inotropic effects: in healthy volunteers, hexarelin increased left ventricular ejection fraction from 64.0 to 70.7 percent within 15 to 30 minutes of intravenous administration, and in patients with coronary artery disease undergoing bypass surgery, hexarelin produced prompt increases in left ventricular ejection fraction, cardiac index, and cardiac output lasting up to 90 minutes [11, 12].

Beyond the cardiovascular system, hexarelin has demonstrated neuroprotective activity in preclinical models. In a rat model of neonatal hypoxia-ischemia, hexarelin reduced brain damage by 39 percent in the cerebral cortex, hippocampus, and thalamus through Akt/glycogen synthase kinase-3-beta phosphorylation and caspase-3 suppression [13]. In neuroblastoma cell lines, hexarelin modulated MAPK and PI3K/Akt pathways to inhibit hydrogen peroxide-induced apoptotic toxicity [14].

Pharmacokinetically, hexarelin has a plasma elimination half-life of approximately 55 to 70 minutes in humans after parenteral administration. The compound is administered predominantly by subcutaneous injection at research doses of 1 to 2 micrograms per kilogram (approximately 100 to 300 micrograms per administration in adults). Principal adverse effects are dose-dependent and include transient flushing, mild cortisol and prolactin elevation (more pronounced than ipamorelin but less clinically significant than early reports suggested), increased appetite, and water retention. The cortisol and prolactin elevations reflect direct GHS-R1a activation on corticotroph and lactotroph cells and are the principal pharmacodynamic distinction from the more selective secretagogue ipamorelin. No galactorrhea, Cushingoid features, or clinically significant endocrine adverse events have been reported in any published hexarelin study. This monograph documents the chemistry and synthesis, dual-receptor pharmacology, comprehensive pharmacokinetics, the clinical and preclinical evidence base across neuroendocrine, cardiovascular, and neuroprotective applications, sourcing and quality verification, reconstitution and handling, stack-interaction considerations, adverse-event signal, and a structured comparative assessment of five growth hormone secretagogue candidates against hexarelin on five competency standards.