Ipamorelin selectivity study 1998 by Raun explained

The ipamorelin selectivity study by Kirsten Raun and colleagues was published in November 1998 in the European Journal of Endocrinology. Its title is Ipamorelin, the first selective growth hormone secretagogue. The authors worked in the Department of GH Biology at Novo Nordisk in Denmark, the company that developed the compound. This is the original paper that introduced ipamorelin to the scientific literature, and the word selective in its title is the reason the peptide is still discussed today. This article explains what the researchers were trying to achieve, how they tested the compound in cells and animals, what they measured and what the study could not show.

What the ipamorelin selectivity study asked

In the 1990s, several synthetic peptides were known to trigger growth hormone (GH) release from the pituitary gland. The best known were the growth hormone releasing peptides GHRP-6 and GHRP-2. They worked well, but they had a drawback: they also raised the stress hormones ACTH and cortisol, and in some cases prolactin. A compound that released GH without these side signals would be a cleaner research tool and a better drug candidate.

The authors therefore asked two questions. First, could they find a new peptide with GH releasing potency similar to GHRP-6? Second, would that peptide be selective, meaning that it would leave other pituitary hormones untouched? The background on how ipamorelin is usually studied alongside a GHRH analogue is in our guide on CJC-1295 and ipamorelin.

How the ipamorelin selectivity study was done

Ipamorelin came out of a large chemistry programme. The researchers took GHRP-1 as a starting point and made a series of compounds that lacked its central dipeptide, Ala-Trp. Ipamorelin was identified within this series. It is a pentapeptide, a chain of five building blocks, with the sequence Aib-His-D-2-Nal-D-Phe-Lys-NH2. Two of the building blocks are D-amino acids and one, Aib, is not found in natural proteins, which makes the peptide more resistant to breakdown.

The compound was then tested in three systems:

• In vitro: primary rat pituitary cells in culture, to measure GH release directly and to check which receptor was involved using GHRP and GHRH antagonists.

• Anaesthetised rats: to measure GH release in a living animal.

• Conscious pigs: to measure GH release and, importantly, the effect on other hormones: FSH, LH, prolactin, TSH, ACTH and cortisol.

In each system, ipamorelin was compared with GHRP-6, and in pigs also with GHRP-2 and GHRH. The abstract does not state the number of animals per group, so we do not give one.

What the ipamorelin selectivity study found

The abstract reports detailed numbers, which we list here as published:

• Rat pituitary cells: Ipamorelin released GH with an EC50 of 1.3 plus or minus 0.4 nmol/l and a maximum effect of 85 plus or minus 5 percent, compared with 2.2 plus or minus 0.3 nmol/l and 100 percent for GHRP-6. The two compounds were therefore similar in potency and efficacy.

• Receptor: Experiments with antagonists showed that ipamorelin, like GHRP-6, stimulates GH release through a GHRP-like receptor and not through the GHRH receptor.

• Anaesthetised rats: Ipamorelin had an ED50 of 80 plus or minus 42 nmol/kg and a maximum GH level of 1545 plus or minus 250 ng/ml, compared with 115 plus or minus 36 nmol/kg and 1167 plus or minus 120 ng/ml for GHRP-6.

• Conscious pigs: Ipamorelin had an ED50 of 2.3 nmol/kg and a maximum GH level of 65 ng/ml plasma. GHRP-6 gave 3.9 nmol/kg and 74 ng/ml. GHRP-2 was more potent but less effective, with 0.6 nmol/kg and 56 ng/ml.

• Other hormones: None of the compounds tested affected FSH, LH, prolactin or TSH in pigs. GHRP-6 and GHRP-2 both raised ACTH and cortisol. Ipamorelin did not raise ACTH or cortisol to levels significantly different from those seen after GHRH. This held true even at doses more than 200 times higher than the ED50 for GH release.

The authors concluded that ipamorelin was the first GHRP receptor agonist with a selectivity for GH release similar to that of GHRH itself, and they described it as an interesting candidate for clinical development.

Limitations of the ipamorelin selectivity study

• Animal and cell data only: The study used rat cells, rats and pigs. No humans were involved.

• Industry authorship: All authors were employees of the company that developed the compound and held the patent. This is normal for a discovery paper but means the study was not independent.

• Acute measurements: The experiments measured hormone responses after single doses. The paper does not describe repeated dosing or long-term effects.

• Unknown group sizes: The abstract does not report how many animals were used in each experiment.

• Later development: Ipamorelin was taken into clinical trials for a gastrointestinal indication but was not approved as a medicine. The selectivity finding in animals has not been confirmed in a published long-term human trial.

What this means for ipamorelin research

This paper established the two properties that define ipamorelin in the literature: GH releasing potency comparable to GHRP-6, and a lack of effect on ACTH and cortisol in pigs at the doses tested. For researchers, the numerical data in the abstract are a useful reference for designing experiments in pituitary cell cultures or rodent models, and the receptor work explains why ipamorelin is grouped with the GHRP class and not with GHRH analogues.

The study does not show effects in humans and does not support any use outside controlled research. Ipamorelin is most often studied together with a GHRH analogue, because the two act on different receptors. The compounds in this field are listed in our growth hormone peptides collection, and our CJC-1295 and ipamorelin blend is supplied as lyophilised powder for laboratory research. Handling steps are described in our guide on how to reconstitute peptides.

Sources

• Raun K, Hansen BS, Johansen NL, Thogersen H, Madsen K, Ankersen M, Andersen PH (1998). Ipamorelin, the first selective growth hormone secretagogue. European Journal of Endocrinology, 139(5), 552-561. doi:10.1530/eje.0.1390552

This article summarises published research for information only. It is not medical advice. All products on this site are sold for laboratory research use only and are not intended for human or veterinary use.