Ipamorelin vs CJC-1295: two receptors, one axis

The short version

Ipamorelin and CJC-1295 act on the same hormone, growth hormone, through two different receptors. Ipamorelin is a five-residue peptide that activates the ghrelin receptor, GHS-R1a, the receptor through which the growth-hormone-releasing peptides work. CJC-1295 without DAC, also called modified GRF(1–29), is a 29-residue analogue of growth-hormone-releasing hormone that activates the GHRH receptor. The two receptors sit on the same pituitary cells and their signals add together, which is the reason the pair is so often studied in combination and the reason we also list them as a blend. Neither is a licensed medicine.

Both are supplied by BuyUK Peptides as research chemicals for in-vitro laboratory use only. Nothing here is guidance for any other use.

Receptors and mechanism

The GHRH receptor is the physiological "on" switch for growth-hormone release: hypothalamic GHRH binds it on pituitary somatotrophs and raises cAMP. Native GHRH(1–29), the shortest fully active fragment, is cleaved by dipeptidyl peptidase-4 within minutes [1]. CJC-1295 without DAC carries four substitutions, D-alanine at position 2 among them, that were developed to resist that cleavage and the deamidation that limits the stability of the native sequence in solution [2].

The ghrelin receptor was identified in 1996 as the target of the synthetic growth-hormone secretagogues [3]. Ipamorelin was described by Raun and colleagues in 1998 as the first secretagogue in the class to release growth hormone selectively: in their experiments it did so without the rise in ACTH and cortisol that GHRP-6 and GHRP-2 produced at comparable potency [4]. That selectivity is the property that defines it.

The two pathways converge on the same cells, and growth-hormone release in response to the two signals together is synergistic in many of the systems studied rather than simply additive. That is the pharmacological rationale for studying them together.

Structure and chemistry

The two could hardly be more different in size, and that makes them easy to tell apart on a certificate: a mass near 712 Da is ipamorelin, a mass near 3,368 Da is CJC-1295 without DAC.

CJC-1295 with DAC and without: not the same compound

The name CJC-1295 properly belongs to a different molecule. The compound described by Jetté and colleagues at ConjuChem carries an additional lysine bearing a maleimidopropionyl group, the "drug affinity complex" or DAC, which forms a covalent bond with albumin after administration and extends the half-life from minutes to days [5]. In healthy volunteers that molecule raised growth hormone and IGF-1 for a week or more after a single administration [6], and growth-hormone secretion stayed pulsatile despite the continuous stimulation [7].

The peptide sold in research catalogues as "CJC-1295 no DAC" or "modified GRF(1–29)" is the tetrasubstituted GRF(1–29) without that group. It has a half-life of the order of half an hour, and the week-long human data for CJC-1295 with DAC do not apply to it. A certificate should state which molecule it covers, and the mass makes it unambiguous: about 3,368 Da without DAC, about 3,647 Da with it.

The research record

Ipamorelin's record includes the original selectivity work [4], a pharmacokinetic and pharmacodynamic study in healthy volunteers [8], a body of rodent work on bone growth, and a clinical programme by Helsinn for postoperative ileus, in which it was developed as a ghrelin mimetic for gut motility rather than for growth hormone, on the strength of rodent work showing faster recovery of gut transit [9]. The phase 2 trial did not meet its primary endpoint and development stopped [10].

CJC-1295 without DAC has a thinner record of its own. The stability and potency work behind the tetrasubstituted analogue comes from the GRF analogue programmes of the late 1980s and 1990s [2]; most later literature concerns either native GHRH(1–29), which is sermorelin, or the DAC-bearing molecule. Researchers using the no-DAC peptide are working with a compound whose pharmacology is inferred more from its relatives than measured directly.

Regulatory and anti-doping status in the UK

Neither compound is a licensed medicine in the UK or anywhere else, and neither is a controlled drug. Both are supplied here as chemicals for in-vitro laboratory use under the Terms of Sale; our guide to the UK rules sets out the position. Both are prohibited in sport at all times under the WADA Prohibited List's section S2.2, which covers GHRH and its analogues and the growth-hormone secretagogues and their mimetics.

Handling at the bench

Ipamorelin is small, hydrophilic and robust: it dissolves at once in water or bacteriostatic water and keeps well refrigerated in solution. CJC-1295 without DAC is longer and dissolves more slowly. Its substitutions replace the asparagine and methionine that make native GHRH(1–29) unstable in solution, so it keeps better than sermorelin, but as a 29-residue peptide it still benefits from cold storage and prompt aliquoting once reconstituted. Some laboratories find it goes into solution more cleanly in dilute acetic acid before dilution into buffer. Both should be stored sealed at 2 to 8 °C, or −20 °C for the long term, and brought to room temperature before opening. Choosing a reconstitution solvent covers both.

What to look for on the certificate

For ipamorelin, RP-HPLC purity of 98 per cent or above and an LC-MS identity line at about 711.9 Da, usually seen as the singly charged ion at m/z 712.4 or the doubly charged at 356.7. For CJC-1295 without DAC, purity of 98 per cent or above and a deconvoluted mass of about 3,367.9 Da, with the main charge states at m/z 1,123.6 (3+) and 843.0 (4+). The most important check on a CJC-1295 certificate is that the mass matches the no-DAC molecule you ordered. For the blend, the certificate should report each component separately.

Which to choose

For a question about ghrelin-receptor pharmacology, ipamorelin is the cleanest ligand in the catalogue because of its documented selectivity. For a question about the GHRH receptor, CJC-1295 without DAC or sermorelin is the tool, and sermorelin vs tesamorelin sets out the GHRH analogues. For work on the interaction between the two receptor systems, use both, ideally as separate vials so the ratio can be varied. Full accounts are in the monographs for ipamorelin and CJC-1295 without DAC.

References

1. Frohman LA, Downs TR, Williams TC, Heimer EP, Pan YC, Felix AM. Rapid enzymatic degradation of growth hormone-releasing hormone by plasma in vitro and in vivo to a biologically inactive product cleaved at the NH2 terminus. Journal of Clinical Investigation. 1986;78(4):906–913. doi:10.1172/JCI112679.
2. Campbell RM, Stricker P, Miller R, et al. Enhanced stability and potency of novel growth hormone-releasing factor (GRF) analogues derived from rodent and human GRF sequences. Peptides. 1994;15(3):489–495. doi:10.1016/0196-9781(94)90211-9.
3. Howard AD, Feighner SD, Cully DF, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996;273(5277):974–977. doi:10.1126/science.273.5277.974.
4. Raun K, Hansen BS, Johansen NL, et al. Ipamorelin, the first selective growth hormone secretagogue. European Journal of Endocrinology. 1998;139(5):552–561. doi:10.1530/eje.0.1390552. PMID 9849822.
5. Jetté L, Léger R, Thibaudeau K, et al. Human growth hormone-releasing factor (hGRF)1–29-albumin bioconjugates activate the GRF receptor on the anterior pituitary in rats: identification of CJC-1295 as a long-lasting GRF analog. Endocrinology. 2005;146(7):3052–3058. doi:10.1210/en.2004-1286.
6. Teichman SL, Neale A, Lawrence B, Gagnon C, Castaigne JP, Frohman LA. Prolonged stimulation of growth hormone (GH) and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults. The Journal of Clinical Endocrinology & Metabolism. 2006;91(3):799–805. doi:10.1210/jc.2005-1536.
7. Ionescu M, Frohman LA. Pulsatile secretion of growth hormone (GH) persists during continuous stimulation by CJC-1295, a long-acting GH-releasing hormone analog. The Journal of Clinical Endocrinology & Metabolism. 2006;91(12):4792–4797. doi:10.1210/jc.2006-1702.
8. Gobburu JVS, Agersø H, Jusko WJ, Ynddal L. Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharmaceutical Research. 1999;16(9):1412–1416. doi:10.1023/A:1018955126402. PMID 10496658.
9. Venkova K, Mann W, Nelson R, Greenwood-Van Meerveld B. Efficacy of ipamorelin, a novel ghrelin mimetic, in a rodent model of postoperative ileus. Journal of Pharmacology and Experimental Therapeutics. 2009;329(3):1110–1116. doi:10.1124/jpet.108.149211.
10. Beck DE, Sweeney WB, McCarter MD; Ipamorelin 201 Study Group. Prospective, randomized, controlled, proof-of-concept study of the ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients. International Journal of Colorectal Disease. 2014;29(12):1527–1534. doi:10.1007/s00384-014-2030-8.

This monograph summarises the published literature for laboratory researchers. It is not medical advice, and nothing on this site is for human or veterinary use.