Hexarelin

Molecular identity

Sequence

His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2

Formula

C47H58N12O6

Molecular weight

887.0 g/mol

CAS

140703-51-1

PubChem CID

6918297

What it acts on

• GHS-R1a, the ghrelin receptor — the reviews describe hexarelin binding and activating this G-protein-coupled receptor much as ghrelin does; engagement is associated in vitro with Gq/phospholipase-C signalling and intracellular calcium mobilisation, and in the rat ischaemia/reperfusion study it was the IL-1β and IL-1Ra expression changes that were neutralised by a GHSR antagonist.
• CD36 scavenger receptor — photoaffinity labelling of rat cardiac membranes identified the hexarelin binding protein as a glycoprotein of about 84 kDa whose N-terminal sequence was CD36, expressed in cardiomyocytes and microvascular endothelial cells; the site is competed by peptidyl GHRPs but not by the non-peptidyl secretagogue MK-677.
• Coronary vascular tone through CD36 — in isolated perfused hearts, activation of CD36 by hexarelin raised coronary perfusion pressure in a dose-dependent manner, a response absent in CD36-null hearts and in CD36-deficient spontaneously hypertensive rats.
• Interleukin-1 signalling in ischaemic myocardium — the in vivo rat study reports down-regulated IL-1β and up-regulated IL-1Ra protein in reperfused myocardium, an effect neutralised by GHSR blockade.
• Pituitary hormone output — the class review notes that GHRPs release growth hormone strongly and reproducibly but also release prolactin and ACTH/cortisol, so the class is not endocrine-selective.

What the studies report

Each item below summarises the paper it is numbered to, written from that paper's own abstract. The badge says how the evidence was produced.

1. 1.
   reviewJ Geriatr Cardiol (2014)

   A concise narrative review of the cardiovascular literature. It sets out the two-receptor picture — GHS-R1a in the brain, as for ghrelin, plus peripheral GHSR distribution in heart and vessels, and the non-GHSR receptor CD36 described as the specific cardiac receptor mediating cardioprotective effects — and states that hexarelin is chemically more stable and functionally more potent than ghrelin. The therapeutic framing is explicitly prospective (the compound 'may be' a promising agent), and the piece assembles existing evidence rather than generating any of its own.

2. 2.
   reviewAnn Endocrinol (Paris) (2000)

   A review of the GHRP class. It reports strong, dose-dependent and reproducible growth-hormone release but also significant prolactin and ACTH/cortisol release, so the class is not endocrine-selective; effects on food intake and sleep pattern are noted as well. Radiolabelled Tyr-Ala-hexarelin mapped binding to pituitary, hypothalamus and extra-hypothalamic brain regions, and to heart, adrenal, ovary, testis, lung and skeletal muscle at higher density than the hypothalamo-pituitary system, with human cardiovascular binding highest in ventricles; cardiac membrane binding was displaced by peptidyl GHRPs but not by MK-677. The review further cites anti-apoptotic activity in H9c2 cells, protection from ischaemia-induced myocardial damage in aged and GH-deficient rats, and a positive inotropic effect in human subjects — but only as summary statements, without the designs, sample sizes or controls of the underlying studies.

3. 3.
   in vitroCirc Res (2002)

   The paper that identified CD36. Rat cardiac membranes were labelled with a radioactive photoactivatable hexarelin derivative and purified by lectin affinity chromatography and preparative gel electrophoresis, yielding a binding protein of about 84 kDa whose deglycosylated N-terminal sequence was identical to rat CD36, a multifunctional glycoprotein expressed in cardiomyocytes and microvascular endothelial cells. In isolated perfused hearts, CD36 activation raised coronary perfusion pressure dose-dependently; the response was absent in hearts from CD36-null mice and from spontaneously hypertensive rats genetically deficient in CD36, and correlated with CD36 expression on immunoblot. This is receptor-identification work on membranes and perfused organs rather than whole-animal treatment, and the authors' extension to coronary vasospasm in hypercholesterolaemia and atherosclerosis is offered as a suggestion, not a demonstration.

4. 4.
   animal modelInt Heart J (2017)

   An in vivo rat study of myocardial ischaemia/reperfusion: male Sprague-Dawley rats underwent left coronary artery ligation followed by reperfusion, then received hexarelin, an equimolar comparison with ghrelin, or saline, with assessment by echocardiography, malondialdehyde measurement, histochemical staining and Western blot. The report describes improved cardiac systolic function, decreased malondialdehyde, more surviving cardiomyocytes, down-regulated IL-1β and up-regulated IL-1Ra in the reperfused myocardium, with the overall benefit called slightly superior to equimolar ghrelin; it is the IL-1β and IL-1Ra expression changes, not the functional readouts, that the report shows to be neutralised by the GHSR antagonist [D-Lys3]-GHRP-6. The authors themselves describe the mechanism as partial — protection 'partly by modification of the IL-1 signalling pathway' — and the study rests on a single species and a single model, with no human arm.

Used in research on