GHRP-2: Discovery and Regulatory History

Introduction

The development of GHRP-2 (pralmorelin) represents a convergence of three independent lines of biomedical research: the chemistry of synthetic opioid analogs, the pharmacology of growth hormone regulation, and the molecular biology of orphan G protein-coupled receptors. The compound's history spans approximately four decades — from foundational enkephalin studies in the mid-1970s to its regulatory approval in Japan in 2004 as the first growth hormone secretagogue sanctioned for clinical diagnostic use. This article traces that history in chronological sequence, drawing on published primary literature and regulatory documents.

Discovery Period: Enkephalin Analogs and Pituitary GH Release (1977–1984)

The scientific lineage of GHRP-2 begins with observations made by Cyril Y. Bowers and colleagues at Tulane University in the late 1970s. Working with synthetic analogs of met-enkephalin — an endogenous opioid pentapeptide — Bowers' group observed that certain chemical modifications produced selective GH-releasing activity in rat pituitary cell cultures without meaningful opioid receptor agonism. This finding indicated the existence of a novel secretagogue pathway distinct from then-known mechanisms of GH regulation.

A key structure-activity publication from 1980 in Endocrinology by Bowers, Momany, Reynolds, Chang, Hong, and Chang described the pharmacological properties of a synthetic pentapeptide (Tyr-D-Trp-Gly-Phe-Met-NH2), which produced selective GH release from rat pituitary cultures at low concentrations. The study emphasized that an aromatic amino acid residue at position 2 of the peptide was critical for GH-releasing potency — a structural insight that would guide all subsequent compound optimization [1].

The program culminated in 1984 with the report of GHRP-6, the first synthetic hexapeptide growth hormone-releasing peptide, in a study by Bowers, Momany, Reynolds, and Hong published in Endocrinology. GHRP-6 (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) demonstrated potent in vitro and in vivo GH release in multiple species [2] and became the reference compound from which the broader GHRP family — including GHRP-1, GHRP-2, and hexarelin — was subsequently derived. The parallel discovery history of GHRP-6 traces this same foundational lineage from a related vantage point.

Early Research: Structural Optimization and Identification of GHRP-2 (Late 1980s–Early 1990s)

Following publication of the GHRP-6 structure, research groups including Bowers' laboratory and Kaken Pharmaceutical in Japan pursued further structure-activity optimization. The substitution of D-2-naphthylalanine (D-2-Nal) at position 2 — replacing GHRP-6's D-tryptophan residue — produced a compound with substantially greater GH-releasing potency. This compound, with the sequence D-Ala-D-2Nal-Ala-Trp-D-Phe-Lys-NH2, became GHRP-2, designated KP-102 by Kaken Pharmaceutical.

The structural rationale for enhanced potency at the D-2-Nal position related to the larger hydrophobic surface area of the naphthyl ring system relative to the indole ring of tryptophan, improving hydrophobic contacts within the receptor binding site — consistent with Bowers' 1980 insight about the importance of aromatic character at position 2.

During this period, the broader GHS field was rapidly expanding. Romano Deghenghi and colleagues at Europeptides were developing hexarelin (His-D-2-MeTrp-Ala-Trp-D-Phe-Lys-NH2), while Merck Research Laboratories was pursuing the first non-peptidyl GHS compounds, leading ultimately to MK-0677/ibutamoren. The separate GHRH analog development pathway — which produced compounds such as tesamorelin — proceeded concurrently through distinct chemistry and regulatory routes. The 1990s saw multiple parallel research programs recognizing the therapeutic and diagnostic potential of GHS pharmacology.

Regulatory Milestones

1996: Cloning of the GHS Receptor

A pivotal event in the history of the GHRP class was the molecular cloning of the growth hormone secretagogue receptor (GHS-R1a) by Howard and colleagues at Merck Research Laboratories, published in Science in 1996. This work established the molecular target for all synthetic GHSs, demonstrated receptor expression in pituitary and hypothalamic tissue, and opened the receptor to systematic pharmacological and structural investigation [3].

The cloning of GHS-R1a transformed understanding of GHRP-2: the compound was now definitively characterized as a full agonist at a defined GPCR, and its pharmacological profile could be interpreted within a rigorous receptor-pharmacology framework rather than purely empirical observation.

1999: Discovery of Ghrelin

Three years after GHS-R1a was cloned as an orphan receptor, Masayasu Kojima, Kenji Kangawa, and colleagues at Kurume University and National Cardiovascular Center Research Institute (Japan) isolated the endogenous ligand for GHS-R1a from rat stomach tissue. The peptide — named ghrelin, from the Proto-Indo-European root for "grow" — was a 28-amino acid acylated hormone produced primarily in the gastric fundus. The discovery was published in Nature in 1999 [4].

Ghrelin's discovery retroactively established that synthetic GHSs such as GHRP-2 had, since their inception, been acting as pharmacological mimics of an endogenous hormone whose existence was unknown during the initial development of the compound class. This insight reframed the GHRP field within the physiology of a biologically important hormonal receptor system with documented roles in GH secretion, appetite regulation, and energy homeostasis.

2004: PMDA Approval in Japan

Kaken Pharmaceutical submitted pralmorelin for regulatory review to Japan's Pharmaceuticals and Medical Devices Agency. The application was supported by comprehensive preclinical pharmacological characterization [5, 6] and multicenter clinical trial evidence demonstrating that intravenous pralmorelin challenge reliably discriminated between severely GH-deficient patients and healthy controls based on peak GH response [7].

In October 2004, PMDA granted regulatory approval for pralmorelin (brand name GHRP Kaken) as a diagnostic agent for the assessment of growth hormone deficiency in adults and in children aged four years and older. This approval made pralmorelin the first — and as of the date of this article, the only — growth hormone secretagogue to receive national regulatory approval for clinical use by any regulatory authority. The diagnostic indication covers a single intravenous GH stimulation test to assess pituitary somatotroph reserve.

International Clinical Development Context

Wyeth-Ayerst Laboratories licensed North American development rights for GHRP-2 from Kaken Pharmaceutical during the 1990s and conducted Phase II clinical trials in the United States, building an international evidence base for the compound's pharmacological profile. This work contributed to the broader scientific literature on GHS diagnostic utility. Development priorities were subsequently reallocated, and no NDA was filed for any indication with the FDA. In Europe, the related compound hexarelin was studied in clinical contexts, with both programs contributing to the growing body of evidence informing GHS receptor pharmacology.

Current Research Landscape

Academic interest in GHRP-2 continues across several active research domains as of the date of this article:

GH deficiency diagnostics. Pralmorelin remains in clinical use in Japan as a diagnostic tool. The pharmacological validation literature, including the 2004 multicenter trial data [7], continues to be cited in endocrinology literature discussing GH stimulation test methodologies.

Ghrelin receptor pharmacology. GHRP-2 serves as a reference pharmacological tool in studies investigating GHS-R1a receptor pharmacology, constitutive receptor activity, biased agonism, and the receptor's physiological roles beyond GH secretion — including appetite, energy homeostasis, and glucose metabolism.

Cytoprotective mechanisms. A research thread initiated in the 1990s and reviewed comprehensively by Berlanga-Acosta and colleagues (2017) has documented cardioprotective, anti-apoptotic, and anti-inflammatory observations for the GHRP family in preclinical models [8]. Ongoing mechanistic work examines whether these effects are GHS-R1a dependent or involve other receptors such as CD36.

Anti-doping science. WADA's prohibition of GHS compounds in competitive sports has generated an ongoing analytical detection literature, exemplified by Okano and colleagues' 2010 LC-MS/MS method for pralmorelin and its urinary metabolites [9]. Synthesis and quality verification standards for research-grade pralmorelin are covered in the GHRP-2 sourcing and quality article.

Historical synthesis. Ishida's 2020 review in JCSM Rapid Communications situated pralmorelin within the broader GHS class history, from enkephalin origins through receptor cloning and regulatory approval [10].

References

1. Bowers CY, Momany F, Reynolds GA, Chang D, Hong A, Chang K. Structure-activity relationships of a synthetic pentapeptide that specifically releases growth hormone in vitro. Endocrinology. 1980;106(3):663–667. PMID: 6109621. DOI: 10.1210/endo-106-3-663

2. Bowers CY, Momany FA, Reynolds GA, Hong A. On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology. 1984;114(5):1537–1545. PMID: 6714155. DOI: 10.1210/endo-114-5-1537

3. Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996;273(5277):974–977. PMID: 8688086. DOI: 10.1126/science.273.5277.974

4. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656–660. PMID: 10604470. DOI: 10.1038/45230

5. Arase K, Ohboshi T, Endo S, Akahane S. Pharmacological characteristics of KP-102 (GHRP-2), a potent growth hormone-releasing peptide. Arzneimittelforschung. 2004;54(12):857–867. PMID: 15646370. DOI: 10.1055/s-0031-1297041

6. Ohboshi T, Arase K, Endo S, Akahane S. General pharmacology of KP-102 (GHRP-2), a potent growth hormone-releasing peptide. Arzneimittelforschung. 2004;54(12):868–876. PMID: 15646371. DOI: 10.1055/s-0031-1297042

7. Kaken Pharmaceutical Co., Ltd. Pralmorelin: GHRP-2, GPA-748, growth hormone-releasing peptide 2, KP-102 D, KP-102 LN. Drugs R D. 2004;5(4):232–235. PMID: 15230633. DOI: 10.2165/00126839-200405040-00008

8. Berlanga-Acosta J, Abreu-Cruz A, García-del Barco Herrera D, Mendoza-Marí Y, Rodríguez-Ulloa A, García-Ojalvo A, et al. Synthetic growth hormone-releasing peptides (GHRPs): a historical appraisal of the evidences supporting their cytoprotective effects. Clin Med Insights Endocrinol Diabetes. 2017;10:1179546817694558. PMID: 28469490. PMC: PMC5392015. DOI: 10.1177/1179546817694558

9. Okano M, Sato M, Kageyama S, Niioka T, Yonezawa K, Suzuki H, et al. Determination of growth hormone secretagogue pralmorelin (GHRP-2) and its metabolite in human urine by liquid chromatography/electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrom. 2010;24(14):2046–2056. PMID: 20552695. DOI: 10.1002/rcm.4619

10. Ishida J, Saitoh M, Doehner W, von Haehling S, Anker SD, Springer J. Growth hormone secretagogues: history, mechanism of action, and clinical development. JCSM Rapid Commun. 2020;3(1):25–37. DOI: 10.1002/rco2.9