Ipamorelin Peptide (10MG)

This 1998 paper in the European Journal of Endocrinology (Raun et al., Novo Nordisk) describes the discovery and pharmacology of ipamorelin. The researchers compared ipamorelin with the reference secretagogues GHRP-6 and GHRP-2, and with GHRH, in three systems:

• Cultured rat pituitary cells
• Anesthetized rats
• Conscious swine

The swine experiments also measured other pituitary and adrenal hormones to test how selective each compound was for GH.

Scope: This was a laboratory and animal pharmacology study. It did not test ipamorelin in people.

• Citation: Raun K, Hansen BS, Johansen NL, et al. Eur J Endocrinol. 1998;139(5):552–561.
• Study type: Discovery and pharmacology (in vitro and in vivo)
• In vitro: Primary rat pituitary cells
• Rats: Male Sprague-Dawley rats under pentobarbital anesthesia, 6 rats per dose level, given an intravenous bolus
• Swine: Conscious female Landrace × Yorkshire swine (about 40 kg), 6 per compound, given an intravenous bolus
• Comparators: GHRP-6, GHRP-2 and GHRH
• Hormones measured in swine: GH, ACTH, cortisol, FSH, LH, prolactin (PRL) and TSH
• Authors: Novo Nordisk A/S researchers

GH is released from the pituitary in pulses. It is controlled mainly by two hypothalamic peptides: GHRH, which stimulates release, and somatostatin, which inhibits it. A third system, the GHRP receptor, can also trigger GH release.

Earlier GHRPs, such as GHRP-6 and GHRP-2, released GH strongly in animals. They also raised ACTH and cortisol, the stress-axis hormones. The Novo Nordisk program aimed to find a GHRP-receptor agonist that releases GH with the selectivity of GHRH itself.

Ipamorelin came from a chemistry series built on GHRP-1, with the central dipeptide Ala-Trp removed. Replacing the N-terminal L-alanine of an earlier analog with Aib (α-aminoisobutyric acid) restored GH-releasing potency and efficacy in vitro and in vivo.

The peptide was made by solid-phase synthesis and purified by reverse-phase HPLC. Its identity was confirmed by NMR and mass spectrometry. It was handled as a water-soluble trifluoroacetate salt with measured pKa values of 10.3, 7.8 and 6.2.

In primary rat pituitary cells, ipamorelin released GH with potency and efficacy similar to GHRP-6. The EC₅₀ was about 1.3 nmol/L for ipamorelin and 2.2 nmol/L for GHRP-6, and the maximal response was about 85% of GHRP-6's.

Tests with receptor antagonists showed that ipamorelin, like GHRP-6, acted through a GHRP-like receptor rather than the GHRH receptor.

Anesthetized rats: Ipamorelin released GH with potency and efficacy comparable to GHRP-6. The ED₅₀ was about 80 nmol/kg for ipamorelin and 115 nmol/kg for GHRP-6. Peak GH was about 1,545 ng/mL and 1,167 ng/mL, respectively.

Conscious swine: Ipamorelin released GH with an ED₅₀ of about 2.3 nmol/kg and a maximal plasma GH of about 65 ng/mL. GHRP-6 was very similar, at 3.9 nmol/kg and 74 ng/mL. GHRP-2 was more potent (ED₅₀ about 0.6 nmol/kg) but reached a lower maximum (about 56 ng/mL).

In swine, none of the secretagogues changed FSH, LH, prolactin or TSH. GHRP-6 and GHRP-2 both increased plasma ACTH and cortisol. Ipamorelin did not raise ACTH or cortisol beyond the levels seen after GHRH. This held even at doses more than 200 times the ED₅₀ for GH release.

The authors described ipamorelin as the first GHRP-receptor agonist with GH selectivity similar to GHRH.

• The study measured acute hormone responses after a single intravenous bolus. It did not examine repeated administration or long-term outcomes.
• Rat experiments were done under anesthesia, which can affect hormone release.
• Selectivity was tested in one species (swine), with 6 animals per compound.
• The study was conducted by the company developing the compound.
• Animal pharmacology does not establish effects, safety or dosing in people.

Raun et al. (1998) reported that ipamorelin released GH through a GHRP-like receptor, with potency and efficacy similar to GHRP-6 in rat pituitary cells, anesthetized rats and conscious swine. Unlike GHRP-6 and GHRP-2, it did not raise ACTH or cortisol beyond GHRH-like levels in swine, even at more than 200 times its GH ED₅₀. FSH, LH, prolactin and TSH were unaffected.

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