Ipamorelin and GHRP-6 had similar EC50 values for GH release in rat pituitary cells. So where did their measured profiles differ? This comparison adds GHRP-2 and looks at peptide structure, receptor pharmacology, swine endocrine measurements and rodent feeding observations. The primary papers are linked below so you can check what each experiment actually measured.
Key findings
- EC50 on rat pituitary cells: 1.3 nmol/L for ipamorelin, 2.2 for GHRP-6 (Raun 1998). Basically a tie.
- In swine, GHRP-6 and GHRP-2 increased ACTH and cortisol. Ipamorelin’s measurements did not differ from the GHRH comparison, even at amounts more than 200 times its GH-release ED50 (Raun 1998).
- Sated rats given GHRP-6 into the ventricles started eating, more so with more peptide, while their plasma GH barely budged (Locke 1995).
- Ipamorelin’s terminal half-life came out near 2 hours in Gobburu’s 1999 PK/PD work.
- In rats, continuous and intermittent GHRP-6 exposure produced different GH-response patterns (Wells and Houston 2001).
One receptor, three keys
Every peptide here turns on GHS-R1a, the growth hormone secretagogue receptor. Funny thing: nobody had cloned it until 1996, a dozen years after GHRP-6 was published (Howard et al., 1996). Ghrelin, the body’s own key for that lock, turned up in stomach extracts in 1999 (Kojima et al., 1999).
So for about fifteen years, people were publishing on GHRP-6 with no idea what it bound. Keep that in mind when you dig through the old stuff.
GHS-R1a is expressed on pituitary somatotrophs and hypothalamic neurons. The studies below measured GH release, other endocrine readouts and feeding behavior in specific experimental models. These endpoints answer different questions and should not be treated as interchangeable measures of receptor selectivity.
Five residues versus six
Start with GHRP-6 (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2), which has a weird backstory. Momany, Bowers and colleagues started from met-enkephalin analogs, opioid-type peptides with no obvious GH link, and found that some modified versions released GH weakly in vitro (Momany et al., 1981). Refining that lead gave them the hexapeptide. By 1984 they had a hexapeptide that let GH out in the dish and in animals, left LH, FSH, TSH and prolactin alone, and worked in rats, monkeys, lambs and calves alike (Bowers et al., 1984).
GHRP-2 has six residues too (D-Ala-D-βNal-Ala-Trp-D-Phe-Lys-NH2), with a bulky naphthylalanine sitting where GHRP-6 keeps its D-Trp. Arvat’s group described GHRP-2 and hexarelin as “super-analogs of GHRP-6” (Arvat et al., 1997).
Ipamorelin is shorter. It’s a pentapeptide, Aib-His-D-2-Nal-D-Phe-Lys-NH2, that came out of a Novo Nordisk chemistry program working on compounds lacking the central Ala-Trp dipeptide of GHRP-1 (Raun et al., 1998). The Aib residue at position 1 and the D-2-naphthylalanine at position 3 are the unusual building blocks here.
Each one carries D-amino acids, and proteases tend to choke on those. We’re stating a general design rule there, not a measured comparison.
Potency: closer than you’d guess
Raun’s group compared all three peptides in cell and animal experiments. The results depended on both the model and the endpoint:
- In rat pituitary cells, ipamorelin’s GH-release EC50 was 1.3 nmol/L and GHRP-6’s was 2.2 nmol/L. Ipamorelin’s maximal response was about 85% of GHRP-6’s.
- In anesthetized rats, the GH-release ED50 was 80 nmol/kg for ipamorelin and 115 nmol/kg for GHRP-6. Maximal GH concentrations were 1,545 and 1,167 ng/mL, respectively.
- In conscious swine, GH-release ED50 values were 0.6 nmol/kg for GHRP-2, 2.3 nmol/kg for ipamorelin and 3.9 nmol/kg for GHRP-6.
In that swine experiment, GHRP-2 had the lowest ED50, but its maximal GH concentration was 56 ng/mL, compared with 65 for ipamorelin and 74 for GHRP-6 (Raun et al., 1998). A lower ED50 and a higher maximum are different assay findings.
You’ll see it said that GHRP-2 has the tightest receptor binding of the three. Maybe so in particular formats, but we couldn’t find a single head-to-head binding paper to cite, so we’re leaving it as an open question rather than a fact.
Selectivity: the real dividing line
ACTH and cortisol
This is where the Raun data get interesting. In swine, none of the three peptides 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, and that held even at exposure levels more than 200-fold above its ED50 for GH release. The authors themselves called it “very surprising” and titled the paper “the first selective growth hormone secretagogue” (Raun et al., 1998).
The swine findings did not establish why these peptides produced different ACTH and cortisol readouts. Biased signaling is one possible explanation, but it was not demonstrated by those measurements. The comparison remains specific to the species and experimental conditions.
Limits of the hormone comparisons
The swine data did not support describing GHRP-2 as more selective than GHRP-6 on the basis of ACTH and cortisol. They also did not establish a general selectivity ranking across species. Endocrine concentrations and receptor-binding selectivity are different endpoints.
GHRP-6 has a second receptor
GHRP-6 also binds CD36, a scavenger receptor on an entirely different pathway. Proulx and colleagues made aza-analogs of GHRP-6 that lost at least 100-fold affinity for GHS-R1a while some kept their CD36 binding, and several of those analogs showed antiangiogenic activity in a choroid sprouting assay (Proulx et al., 2012). You can only split two activities apart if both were there to begin with.
Is that a problem? Depends on the study. If you want a one-receptor tool, it’s a confound. If CD36 biology is your question, GHRP-6 becomes the more interesting molecule. No comparable second target has been reported for ipamorelin.
Feeding observations in rats
In sated rats, ventricular GHRP-6 exposure was followed by feeding, and a larger fraction of animals ate at higher tested amounts (p < 0.01). Plasma GH during the following hour did not show the same relationship (Locke et al., 1995).
In rats, an NPY Y1 receptor antagonist blocked the feeding response to ghrelin and GHRP-6. The researchers observed c-Fos staining in the arcuate and paraventricular nuclei, other hypothalamic and brainstem regions, and orexin cells. These staining patterns were also seen when food was unavailable (Lawrence et al., 2002).
For rodent GH-axis experiments, feeding is a separate endpoint that can complicate interpretation. In feeding-circuit experiments, that endpoint may be central to the question. We did not find a matched feeding study comparing ipamorelin with GHRP-6, so the available evidence does not establish their relative effects in that model.
Half-life and time course
Gobburu’s pharmacokinetic analysis reported a terminal half-life of roughly 2 hours, clearance of 0.078 L/h/kg and a steady-state volume of distribution of 0.22 L/kg. Kinetics were linear over the range examined (Gobburu et al., 1999).
In rats, GH rose within 2 minutes of GHRP-6 exposure, peaked at 10 to 20 minutes and usually returned to baseline by 2 hours (Bowers et al., 1984). That’s a GH-response profile, not a plasma half-life of the peptide itself.
For GHRP-2 we didn’t find a plasma half-life value we could verify against a primary abstract. Rather than repeat a number of unknown origin, we’ve left that cell of the table marked as not established here.
Desensitization in rat experiments
In transgenic growth-retarded rats, continuous GHRP-6 exposure produced a transient growth response and lower GH and corticosterone responses to a later GHRP-6 challenge. Arcuate GHS-R mRNA did not decrease, while periventricular somatostatin mRNA increased. Intermittent exposure produced sustained growth and GH responses (Wells and Houston, 2001).
So the mechanism here may be more about hypothalamic somatostatin tone than receptor loss. That’s a useful detail when you design an experiment around repeated exposure.
In Bowers’ 1984 study, immature rats exposed repeatedly to GHRP-6 for up to 25 days gained more weight than controls, and their pituitaries remained responsive at the study endpoint (Bowers et al., 1984). We did not find a matched comparison establishing whether ipamorelin, GHRP-2 and GHRP-6 differed in desensitization under the same experimental conditions.
Synergy with GHRH
GHRH and the peptides discussed here act at distinct receptors. Cloning of GHS-R1a provided a molecular basis for separating these receptor systems (Howard et al., 1996).
In transgenic growth-retarded rats, Wells and Houston observed greater skeletal growth and lower pituitary GH stores with combined GRF and GHRP-6 exposure than with GHRP-6 alone (Wells and Houston, 2001). Raun’s antagonist experiments indicated that ipamorelin acted through a GHRP-like receptor rather than the GHRH receptor (Raun et al., 1998). For a separate comparison of molecular structure and receptor pharmacology, see our sermorelin vs ipamorelin vs tesamorelin comparison.
Side by side
| Parameter | Ipamorelin | GHRP-6 | GHRP-2 |
|---|---|---|---|
| Structure | Pentapeptide, Aib-His-D-2-Nal-D-Phe-Lys-NH2 | Hexapeptide, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 | Hexapeptide, D-Ala-D-βNal-Ala-Trp-D-Phe-Lys-NH2 |
| Rat pituitary EC50 | 1.3 nmol/L | 2.2 nmol/L | Not reported in Raun et al. |
| Swine ED50 / Emax | 2.3 nmol/kg / 65 ng/mL | 3.9 nmol/kg / 74 ng/mL | 0.6 nmol/kg / 56 ng/mL |
| ACTH / cortisol in swine | Not different from GHRH in swine at more than 200 times the GH-release ED50 | Increased in swine | Increased in swine |
| Prolactin in swine | Not raised in swine | Unchanged in swine | Unchanged in swine |
| Feeding in rodents | No matched data found | Feeding increased in rats; NPY Y1 blockade prevented the response | Less characterized |
| Second receptor | None reported | CD36 | None we could verify |
| Half-life | ~2 h terminal (Gobburu et al., 1999) | GH response back to baseline ~2 h (rats) | Not established here |
Research questions and reported observations
| Research question | Compounds discussed | Evidence summarized |
|---|---|---|
| GH, ACTH and cortisol measurements in swine | Ipamorelin | ACTH and cortisol did not differ from GHRH at more than 200 times the GH-release ED50 in swine |
| Feeding, NPY or orexin circuitry | GHRP-6 | In rats, NPY Y1 antagonism blocked the feeding response |
| CD36 or angiogenesis biology | GHRP-6 (with aza-analog controls) | Dual GHS-R1a/CD36 binding |
| GH and hypothalamic-pituitary-adrenal (HPA) readouts in swine | GHRP-2 | Lowest GH-release ED50 in the swine comparison; ACTH and cortisol increased, while prolactin was unchanged |
| Replicating classic 1980s and 1990s GHRP work | GHRP-6 | Reference compound of that literature |
| GHS-R1a and GHRH-receptor pharmacology | Ipamorelin, GHRP-6 and GHRP-2 | GHS-R1a and GHRH-R are distinct receptors |
A GHS-R1a antagonist comparison can test whether an experimental signal depends on that receptor. CD36 binding gives GHRP-6 an additional target to consider. Our MK-677 vs ipamorelin comparison discusses a non-peptide GHS-R1a agonist alongside ipamorelin.
Material and documentation
Compound background lives in our library pages for ipamorelin, GHRP-6 and GHRP-2. Each lot is tested by a U.S.-based third-party laboratory, and the certificates of analysis are public: ipamorelin COA, GHRP-6 COA, GHRP-2 COA.
Frequently asked questions
What is the difference between ipamorelin and GHRP-6?
Ipamorelin is a pentapeptide, while GHRP-6 is a hexapeptide. Their GH-release EC50 values were similar in rat pituitary cells. In swine, ACTH and cortisol increased with GHRP-6, while ipamorelin’s measurements did not differ from the GHRH comparison (Raun et al., 1998).
How did GHRP-2 and GHRP-6 compare in swine?
In conscious swine, GHRP-2 had a lower ED50 (0.6 vs 3.9 nmol/kg) but a lower maximal GH response (56 vs 74 ng/mL). More potent, less efficacious, in that model.
What did the swine study report for ipamorelin’s cortisol and prolactin measurements?
In the swine study, prolactin was unchanged for all three peptides. Ipamorelin’s ACTH and cortisol measurements did not differ from the GHRH comparison.
Why does GHRP-6 increase appetite in animal studies?
In rats, an NPY Y1 antagonist blocked the feeding response associated with GHRP-6 exposure. The cited work also reported c-Fos staining in hypothalamic and brainstem regions (Lawrence et al., 2002).
References
- Momany FA, Bowers CY, Reynolds GA, et al. Design, synthesis, and biological activity of peptides which release growth hormone in vitro. Endocrinology. 1981. PMID 6109621
- 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. PMID 6714155
- Bowers CY, Reynolds GA, Durham D, et al. Growth hormone (GH)-releasing peptide stimulates GH release in normal men and acts synergistically with GH-releasing hormone. J Clin Endocrinol Metab. 1990. PMID 2108187
- Locke W, Kirgis HD, Bowers CY, Abdoh AA. Intracerebroventricular growth-hormone-releasing peptide-6 stimulates eating without affecting plasma growth hormone responses in rats. Life Sci. 1995. PMID 8614257
- Howard AD, Feighner SD, Cully DF, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996. PMID 8688086
- 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
- Raun K, Hansen BS, Johansen NL, et al. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998. PMID 9849822
- 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
- Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999. PMID 10604470
- Wells T, Houston PA. Skeletal growth acceleration with growth hormone secretagogues in transgenic growth retarded rats: pattern-dependent effects and mechanisms of desensitization. J Neuroendocrinol. 2001. PMID 11412336
- Lawrence CB, Snape AC, Baudoin FM, Luckman SM. Acute central ghrelin and GH secretagogues induce feeding and activate brain appetite centers. Endocrinology. 2002. PMID 11751604
- Proulx C, Picard É, Boeglin D, et al. Azapeptide analogues of the growth hormone releasing peptide 6 as cluster of differentiation 36 receptor ligands with reduced affinity for the growth hormone secretagogue receptor 1a. J Med Chem. 2012. PMID 22712585
Disclaimer: This content is intended for research purposes only and is not meant to constitute medical advice.
This educational material discusses laboratory research concepts only. Loti Labs products are intended strictly for research and development use and are not for human consumption.
