Ipamorelin: Receptor Pharmacology and Published Measurements

Ipamorelin is a pentapeptide, Aib-His-D-2-Nal-D-Phe-Lys-NH2, and it switches on the same receptor as ghrelin. That receptor, GHS-R1a, was cloned in 1996, and the stomach peptide that normally occupies it turned up three years later. Most of what gets said about ipamorelin online traces back to one 1998 paper from Novo Nordisk, so we went to that paper, pulled the numbers out of it, and put them next to the published work on the hexapeptides it gets compared with. Everything below is linked, so you can check us.

What the molecule is

Five residues. Aib at position one, then His, D-2-Nal, D-Phe and a C-terminal Lys amide. Two of those are not standard amino acids at all: Aib is alpha-aminoisobutyric acid, and D-2-Nal is a D-naphthylalanine. Raun’s group found it inside a chemistry program that was deliberately building compounds without the central Ala-Trp dipeptide of GHRP-1 [1].

So it is a pentapeptide, not a hexapeptide, and it is not a GHRH analogue. That last point matters more than people realize, and we come back to it below.

The D-amino acids and the amidated C-terminus are standard synthetic design choices for slowing proteolysis. We are describing a general principle of peptide chemistry there, not a measured stability comparison, because we could not find a head-to-head stability paper worth citing.

The receptor it binds

GHS-R1a is a rhodopsin-like seven transmembrane G protein coupled receptor. Merck’s group cloned it from swine and human pituitary and hypothalamus in 1996 and showed it was the target of the synthetic secretagogues that had been studied for over a decade by then [3]. Their paper ends by suggesting the compounds were mimicking a hormone nobody had found yet.

They were right. In 1999 Kojima and colleagues purified a 28 amino acid peptide from rat stomach with an octanoyl group on serine 3, named it ghrelin, and showed that the acyl group is required for activity [4]. IUPHAR later made the naming official, and GHS-R1a became the ghrelin receptor [5].

That history is useful context for anyone reading papers from the 1980s and early 1990s. The authors could describe what their compounds did without knowing what they bound.

Why GHS-R1a and the GHRH receptor are not interchangeable

The GHRH receptor is a class B GPCR that signals mainly through cAMP. GHS-R1a is class A and couples through phospholipase C. Cunha and Mayo put both receptors into the same cell line and found that turning on the secretagogue receptor alone did nothing to cAMP, while turning on both together roughly doubled the cAMP response compared with GHRH alone [8]. Two receptors, two signaling arms, one readout that is not simply additive.

Sermorelin and CJC-1295 sit on the GHRH side of that line. Ipamorelin, the GHRPs and ghrelin sit on the other. If you are comparing compounds, receptor identity is the first thing to sort out, and our GHRH versus GHRP overview goes further into that split.

Potency numbers, in order

Raun’s paper is one of the few places where ipamorelin, GHRP-6 and GHRP-2 were run side by side in the same hands, which is why it keeps getting cited. The measurements:

System	Ipamorelin	GHRP-6	GHRP-2
Rat pituitary cells, EC50	1.3 nmol/L (Emax 85 percent)	2.2 nmol/L (Emax 100 percent)	not reported
Anaesthetised rats, ED50	80 nmol/kg (Emax 1545 ng/mL)	115 nmol/kg (Emax 1167 ng/mL)	not reported
Conscious swine, ED50	2.3 nmol/kg (Emax 65 ng/mL)	3.9 nmol/kg (Emax 74 ng/mL)	0.6 nmol/kg (Emax 56 ng/mL)

Read the swine row twice. GHRP-2 is roughly four times as potent as ipamorelin and still produced the smallest peak GH concentration of the three [1]. Potency and efficacy are separate axes, and forum summaries collapse them constantly.

Raun’s group also ran the pharmacological controls properly. Using GHRP and GHRH antagonists, they showed ipamorelin works through the GHRP-like receptor rather than the GHRH receptor [1].

Selectivity, which is the actual story

In swine, none of the secretagogues tested moved FSH, LH, prolactin or TSH. GHRP-6 and GHRP-2 both raised ACTH and cortisol. Ipamorelin did not produce ACTH or cortisol levels different from those seen after GHRH stimulation, and the authors noted this held above 200 times the ED50 for GH release. They called it surprising at the time, and the phrase “the first selective growth hormone secretagogue” in their title comes from exactly this result [1].

The human data on the hexapeptides line up with that picture from the other direction. Arvat and colleagues gave GHRP-2 and hexarelin to young adults and compared them against GHRH, TRH and hCRH. Both peptides raised prolactin, ACTH and cortisol. The prolactin rise was smaller than TRH produced, but the ACTH and cortisol rises were on par with hCRH [6]. Their conclusion was blunt: these compounds are not fully specific.

One caveat we would not skip. The ipamorelin selectivity data are from swine, the hexapeptide data in reference 6 are from people, and the endpoints and sampling schedules differ. Cross-species inference is where a lot of peptide writing quietly goes wrong.

Hexarelin binds something else too

Hexarelin gets compared with ipamorelin a lot, and one finding deserves a mention because it has nothing to do with the pituitary. Bodart and colleagues labelled rat cardiac membranes with a photoactivatable hexarelin derivative, purified the binding protein, and sequenced it as CD36, a glycoprotein expressed in cardiomyocytes and microvascular endothelial cells. In perfused hearts from CD36-null mice, the coronary perfusion pressure response to hexarelin was absent [7]. Ipamorelin has no comparable published CD36 result that we could find. Different scaffold, different off-target profile.

Pharmacokinetics

The half-life everyone quotes, about 2 hours, comes from Gobburu and colleagues, who modelled ipamorelin pharmacokinetics and GH responses in healthy male volunteers across five infusion rates. The pharmacokinetics were proportional across the range tested, clearance was 0.078 L/h/kg, steady-state volume of distribution 0.22 L/kg. GH came as a single episode peaking around 0.67 hours and then falling away. The modelled SC50 for half maximal GH stimulation was 214 nmol/L, and individual variability in the pharmacodynamic parameters was wider than in the pharmacokinetic ones [2].

That last detail is the one we would hold onto. The peptide concentration curve was tidy. The hormone response to it was not.

How purity gets established

None of these numbers mean much if the material in the vial is not what the label says. Peptide identity and purity are normally established by reversed phase HPLC for the chromatographic purity figure and mass spectrometry for the molecular mass, with the expected monoisotopic mass of the pentapeptide checked against what the instrument reports. A purity percentage describes one sample, measured by one method, on one date, which is why the certificate of analysis matters more than the number in isolation. Ours are posted at wholesalepeptide.com/coas, and every batch is tested by a U.S.-based third-party laboratory. If you want the longer version of how that testing works, see our page on third-party tested material.

Frequently asked questions

What is ipamorelin’s sequence?

Aib-His-D-2-Nal-D-Phe-Lys-NH2, a pentapeptide with an amidated C-terminus, as described in the 1998 paper that introduced it [1].

Is ipamorelin a GHRH analogue?

No. It acts at GHS-R1a, the ghrelin receptor, which antagonist experiments confirmed [1]. Sermorelin and CJC-1295 are the GHRH analogues, and we cover those in our Sermorelin and CJC-1295 comparison.

Why is ipamorelin called selective?

Because in the swine experiments it raised GH without raising ACTH or cortisol above what GHRH produced, while GHRP-6 and GHRP-2 raised both [1].

References

1. Raun K, Hansen BS, Johansen NL, et al. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998. PMID 9849822
2. Gobburu JV, Agersø H, Jusko WJ, Ynddal L. Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharm Res. 1999. PMID 10496658
3. Howard AD, Feighner SD, Cully DF, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996. PMID 8688086
4. Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999. PMID 10604470
5. Davenport AP, Bonner TI, Foord SM, et al. International Union of Pharmacology. LVI. Ghrelin receptor nomenclature, distribution, and function. Pharmacol Rev. 2005. PMID 16382107
6. Arvat E, di Vito L, Maccagno B, et al. Effects of GHRP-2 and hexarelin, two synthetic GH-releasing peptides, on GH, prolactin, ACTH and cortisol levels in man. Peptides. 1997. PMID 9285939
7. Bodart V, Febbraio M, Demers A, et al. CD36 mediates the cardiovascular action of growth hormone-releasing peptides in the heart. Circ Res. 2002. PMID 11988484
8. Cunha SR, Mayo KE. Ghrelin and growth hormone (GH) secretagogues potentiate GHRH-induced cyclic AMP production in cells expressing transfected GHRH and GH secretagogue receptors. Endocrinology. 2002. PMID 12446584