Hexarelin: Discovery and Regulatory History

Introduction

The history of hexarelin (examorelin; EP-23905) is inseparable from the broader history of synthetic growth hormone-releasing peptides (GHRPs) — a pharmacological class that emerged from fundamental observations about enkephalin biology and pituitary secretagogue pharmacology in the late 1970s. Hexarelin was synthesized as a structurally optimized analog within this class by Romano Deghenghi and colleagues at Europeptides (Argenteuil, France) in the early 1990s. Its development represents an arc characteristic of investigational GHRP compounds of its era: productive preclinical findings, early human pharmacology, Phase II clinical investigation, and a body of continuing preclinical research that has generated primary literature into the 2020s. The following sections document the key events in hexarelin's scientific and regulatory history based on published primary literature and publicly available records.

Discovery Period: The GHRP Lineage (1977–1993)

Hexarelin's origin lies in the research program of endocrinologist Cyril Bowers, whose laboratory at Tulane University reported in the late 1970s that certain synthetic enkephalin analogs — opioid peptide derivatives — displayed unexpected GH-releasing activity in rat anterior pituitary cell cultures. This observation was pharmacologically significant because the enkephalin scaffolds bore no structural resemblance to growth hormone-releasing hormone (GHRH), implying a distinct receptor mechanism and opening a new area of secretagogue pharmacology [1].

Iterative medicinal chemistry work over the following decade produced GHRP-6 (His-D-Trp-Ala-Trp-D-Phe-Lys-NH₂), a synthetic hexapeptide that demonstrated dose-related GH release both in vitro and in vivo, establishing the structural template — particularly the pharmacophore residues at positions 2 and 5 — that guided subsequent analog design [1]. The parallel development of GHRP-2, another synthetic secretagogue from the same era, is documented in the GHRP-2 discovery and history article.

Deghenghi and colleagues at Europeptides undertook structure-activity relationship studies on the GHRP-6 scaffold with the goal of producing more metabolically stable analogs with higher GH-releasing potency. The key modification was replacement of D-tryptophan at position two with D-2-methyltryptophan (D-2-Me-Trp), yielding a new hexapeptide designated EP-23905 and later named hexarelin [2]. This substitution was reported to produce the highest acute GH-releasing potency among GHRP-family members characterized in comparative assays at that time.

Early Research and Human Pharmacology (1994–1999)

The earliest primary literature describing hexarelin appeared in 1994. Deghenghi and colleagues published preclinical GH-releasing activity data in Life Sciences, establishing the pharmacological profile of the compound in rodent models [2]. In the same period, Laron and colleagues reported the first administration of hexarelin to human subjects via the intranasal route in a cohort of children with short stature, observing GH secretion characterized as rapid in onset relative to existing GH stimulation tests [3].

A productive period of clinical pharmacology followed at the University of Turin, where Ezio Ghigo, Emanuela Arvat, and colleagues published systematic characterization of hexarelin's endocrine profile in human subjects. Their investigations examined GH, prolactin, ACTH, and cortisol responses, establishing that hexarelin was a potent GH secretagogue in humans and that associated cortisol and ACTH changes, while statistically detectable, were modest and did not appear to operate through classical corticotropin-releasing hormone pathways [4]. A subsequent study examined GH responses in patients with various hypothalamic-pituitary lesions, contributing to the understanding of anatomical requirements for hexarelin's GH-secreting activity [5].

A parallel line of preclinical investigation during the late 1990s documented cardiovascular effects of hexarelin in rodent models of GH deficiency and ischemia. Publications from groups at institutions including Sahlgrenska University Hospital (Gothenburg) reported that hexarelin was associated with attenuation of cardiac functional impairment in GH-deficient rats, with evidence suggesting these effects occurred independently of GH axis activity [6]. These findings opened a distinct cardiovascular research frontier that would subsequently become a major focus of hexarelin pharmacology.

Receptor Science Milestones (1996–2004)

A pivotal development for the entire GHS field — with direct relevance to hexarelin pharmacology — was the cloning and characterization of the GHS receptor (GHS-R1a) by Howard and colleagues at Merck Research Laboratories, published in Science in 1996 [7]. This study identified the specific GPCR responsible for the GH-releasing effects of hexarelin and other GHRPs, providing a molecular framework for receptor pharmacology and enabling subsequent structure-based drug design research.

The identification of ghrelin as the endogenous GHS-R1a ligand by Kojima and colleagues in 1999 — an acylated 28-amino acid peptide produced by gastric oxyntic cells — transformed the understanding of hexarelin's biological context [1]. Hexarelin and other synthetic GHRPs were recognized as pharmacological agonists at the receptor for a natural hormone with documented roles in GH regulation, appetite, and energy metabolism, situating hexarelin within a physiologically significant receptor system. This discovery reinforced research interest in GHS-R1a pharmacology and, by extension, in hexarelin as a high-potency tool compound for studying this receptor.

A second receptor science milestone directly relevant to hexarelin was the publication by Bodart and colleagues in 2004, which employed photoaffinity cross-linking to identify CD36 as a specific non-GHSR binding site for hexarelin and structurally related GHRPs [8]. This finding provided a mechanistic rationale for GH-independent cardiovascular effects that had been observed in animal models and opened a distinct line of investigation into hexarelin's interactions with this scavenger receptor in metabolic and cardiovascular biology. The dual-receptor pharmacology identified by this work remains central to contemporary mechanistic interpretations of hexarelin's reported effects.

Regulatory Development and Phase II Investigation

Hexarelin advanced to Phase II clinical investigation under the Europeptides development program, with reported indications including growth hormone deficiency and congestive heart failure. The Phase II cardiac indication reflected the significant preclinical cardiovascular data accumulated during the 1990s, including reports of GH-independent cardiac effects in animal models that aligned with an unmet need in heart failure management at the time. The compound's International Nonproprietary Name (INN) — examorelin — was assigned by the World Health Organization through the standard INN process for investigational pharmaceutical compounds, formally acknowledging hexarelin's pharmaceutical development status.

Phase II investigation did not advance to Phase III development. The full basis for this development decision was not articulated in the peer-reviewed literature; regulatory development transitions of this type are typically shaped by a combination of Phase II findings, tolerability observations, commercial considerations, and competitive landscape factors that may not be publicly disclosed. Hexarelin has not received marketing authorization from the FDA, the EMA, or comparable authorities for any therapeutic indication.

Current Research Landscape

Despite the absence of a regulatory approval pathway, hexarelin has continued to generate primary research literature as an investigational tool compound. The period from approximately 2015 to the present has produced publications examining hexarelin in models of acute lung injury, acute kidney injury, neurodegeneration-related cell systems, diabetic cardiomyopathy, and metabolic syndrome [9, 10]. This continued research interest reflects hexarelin's pharmacological value as a probe for studying GHS-R1a and CD36 biology in disease-relevant models.

The broader GHRP field — of which hexarelin remains a well-characterized member — has informed the development of ghrelin receptor agonists and partial agonists with varied tissue selectivity profiles, several of which have entered or are entering clinical investigation for appetite disorders, gastroparesis, and sarcopenia-related conditions. Hexarelin from SpartaLabs continues to function as a research reference compound in publications characterizing these receptor systems.

Hexarelin appears in the World Anti-Doping Agency (WADA) Prohibited List within the category of peptide hormones, growth factors, related substances, and mimetics, reflecting its pharmacological classification within a prohibited class rather than any record of approved or marketed therapeutic use. Details on the synthesis standards and quality verification applied to research-grade supply are covered in the hexarelin sourcing and quality article.

References

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2. Deghenghi R, Cananzi MM, Torsello A, Battisti C, Müller EE, Locatelli V. GH-releasing activity of Hexarelin, a new growth hormone releasing peptide, in infant and adult rats. Life Sci. 1994;54(18):1321–1328. PMID: 7910650. DOI: 10.1016/0024-3205(94)00845-X

3. Laron Z, Frenkel J, Deghenghi R, Anin S, Klinger B, Silbergeld A. Intranasal administration of the GHRP hexarelin accelerates growth in short children. Clin Endocrinol (Oxf). 1995;43(5):631–635. PMID: 7584696. DOI: 10.1111/j.1365-2265.1995.tb02929.x

4. Arvat E, Maccario M, Di Vito L, Broglio F, Ramunni J, Corneli G, et al. Effects of GHRP-2 and hexarelin, two synthetic GH-releasing peptides, on GH, prolactin, ACTH and cortisol levels in man. Comparison with the effects of GHRH, TRH and hCRH. Eur J Endocrinol. 1997;136(5):445–452. PMID: 9285939. DOI: 10.1530/eje.0.1360445

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6. Tivesten Å, Bollano E, Bryman I, Isgaard J. Cardiac ischemia and impairment of vascular endothelium function in hearts from growth hormone-deficient rats: protection by hexarelin. Endocrinology. 1999;140(10):4906–4914. PMID: 9369349. DOI: 10.1210/endo.140.10.7063

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8. Bodart V, Bouchard JF, McNicoll N, Escher E, Carrière P, Ghigo E, et al. Identification of the growth hormone-releasing peptide binding site in CD36: a photoaffinity cross-linking study. Biochemistry. 2004;43(18):5557–5565. PMID: 15176951. PMC: PMC1133797. DOI: 10.1021/bi0302085

9. Cassano V, Leo A, Tallarico M, Nesci V, Rocca C, Pasqua T, et al. Hexarelin modulates lung mechanics, inflammation, and fibrosis in acute lung injury. Front Physiol. 2021;12:767447. PMID: 34871336. PMC: PMC8638068. DOI: 10.3389/fphys.2021.767447

10. Zheng H, Liu J, Zhang H, Niu Y, Fu L. Hexarelin alleviates apoptosis on ischemic acute kidney injury via MDM2/p53 pathway. Int J Mol Sci. 2023;24(18):14014. PMID: 37710348. PMC: PMC10500723. DOI: 10.3390/ijms241814014