Why Compare Hexarelin and CJC-1295 Without DAC?
Hexarelin and CJC-1295 without DAC are frequently mentioned together since both have been studied in the context of growth hormone signalling. Nevertheless, at a molecular level they are different in terms of their pharmacological approaches.
Hexarelin is a synthetic fragment of a growth hormone secretagogue which acts on the growth hormone secretagogue receptor, this receptor is usually known as GHS-R or GHS-R1a. Although CJC-1295 without DAC is generally characterized in both research and commercial literature as a modified fragment of growth hormone-releasing hormone, the use of this term is not consistently maintained in different sources. It is therefore necessary, in the case of laboratory work, to determine the exact peptide sequence and chemical structure rather than depending just on the name 'CJC-1295 without DAC'.
It is important to make this distinction since the interpretation of the results can be affected by a number of factors including receptor identity, downstream signalling, peptide structure, metabolic stability and the timing of the experiments.
Hexarelin and GHS-R Signalling
Hexarelin is a synthetic hexapeptide which is a member of the growth hormone secretagogue family. Experimental research has found specific binding sites for synthetic growth hormone secretagogues in tissue of the pituitary and hypothalamus, thus supporting the idea of investigating the GHS receptor system in neuroendocrine signalling.
GHS-R is a G protein-coupled receptor which is found in the pituitary and hypothalamus and has also been reported to be present in peripheral tissues. It has been shown by research that stimulation of this receptor leads to the activation of intracellular signalling through phospholipase C and results in changes in intracellular calcium.
Research into hexarelin has also shown that receptor biology can be dynamic; experiments carried out on rats found that hexarelin caused changes in the expression of GHS-R1a messenger RNA in tissue from the pituitary and hypothalamus, the extent of the effects varying depending on age and the experimental conditions.
It therefore makes receptor expression an experimental variable of importance instead of merely assuming that the amount of receptor stays constant.
CJC-1295 Without DAC and GHRH Receptor Biology
CJC-1295 is linked to the growth hormone-releasing hormone, or GHRH, signalling pathway and studies on CJC-1295 have shown that it has an effect on the growth hormone-releasing factor receptor in pituitary tissue.
The GHRH receptor is a member of the class B G protein-coupled receptor family and is found on pituitary somatotroph cells. Its activation is associated with adenylyl cyclase and the formation of intracellular cyclic AMP, this being part of the molecular pathway that regulates the secretion of growth hormone.
Because of the fact that CJC-1295 without DAC needs to be treated with care, the CJC-1295 molecule which has been widely studied in the primary literature has a Drug Affinity Complex that allows it to associate covalently with albumin and greatly alters its pharmacokinetic properties. Although the expression "CJC-1295 without DAC" is generally applied to shorter-acting modified GHRH(1-29) analogues, the number of independent studies in the primary literature that specifically deal with the commercially labelled no-DAC form is much smaller.
Researchers should therefore, in the case of scientific reporting, record the exact sequence, the modifications, the molecular mass and the analytical identity of the material being investigated.
The Key Receptor Difference
The main difference between these compounds lies in their main receptor system.
Hexarelin is investigated as a growth hormone secretagogue acting through the GHS receptor system. CJC-1295 without DAC is investigated in the context of GHRH receptor signalling.
These receptors are part of various GPCR families and set off different intracellular signalling processes.
GHS-R signalling has been associated with phospholipase C activation and intracellular calcium mobilisation. GHRH receptor activation is primarily associated with adenylyl cyclase and cyclic AMP signalling in pituitary somatotrophs.
The two pathways can therefore converge on the broader regulation of growth hormone secretion without being molecularly identical.
This point is especially important when it comes to interpreting experiments which measure circulating growth hormone; a similar measurement at a later stage does not prove that two compounds act via the same receptor or signalling mechanism.
Why Peptide Structure Matters
The sequence of the peptide can have an effect on receptor binding, enzymatic stability, plasma persistence and analytical detection.
Research into GHRH analogues shows that minor alterations in structure can lead to changes in biological activity. Investigations into the GRF(1-29) analogues have looked at the substitutions made all along the peptide sequence and the effects these have on receptor interaction and adenylyl cyclase activation.
CJC-1295 together with its DAC derivative serves as a useful example of the way in which chemical modification can considerably alter pharmacokinetic behaviour; the compound that has been published includes a modification based on maleimido which enables it to associate with serum albumin and as a result has a much longer circulation time than the original GHRH fragment.
The fact that the DAC component is missing alters this structural and pharmacokinetic situation. As a result, data obtained using long-acting CJC-1295 should not be taken automatically as direct evidence in support of every substance described as CJC-1295 without DAC.
This is one of the most important limitations when reviewing online peptide literature.
Hexarelin and GHRH Signalling Can Interact
Even though Hexarelin and GHRH-related compounds operate via different receptor systems, experimental research shows that the pathways which regulate the secretion of growth hormone are connected.
Studies which have used growth hormone secretagogues have shown that there is an interaction between GHRH signalling and GHS activity. Experiments carried out on animals have revealed that disrupting GHRH signalling could decrease the growth hormone response to a growth hormone-releasing peptide.
Research carried out by humans has also looked into Hexarelin in conjunction with GHRH, showing that the endocrine response to stimulation by secretagogues cannot always be regarded as being due to a single isolated pathway.
It does not follow that Hexarelin and a GHRH analogue can be regarded as interchangeable; rather, it shows that an analysis at the receptor level and at the pathway level is more informative than comparing the compounds merely on the basis of their downstream hormone measurements.
Experimental Endpoints in Hexarelin Research
The studies involving hexarelin have looked at a number of measurable endpoints.
Growth hormone concentrations are usually investigated since the substance has the ability to stimulate the secretion of growth hormone; nevertheless, various studies published in the literature have also looked at prolactin, ACTH, cortisol, receptor expression and intracellular signalling.
Research carried out on healthy volunteers showed that Hexarelin could affect a number of endocrine measurements rather than causing a single growth hormone response. Furthermore, other studies have looked at GHS receptor binding in human pituitary, hypothalamic and peripheral tissues.
It is important to take this more comprehensive view of the endocrine system into account when interpreting experimental results since one biomarker cannot always be used to describe the full biological activity of a peptide.
Experimental Endpoints in CJC-1295 Research
Research into CJC-1295 has on many occasions looked at growth hormone and IGF-1 as downstream endocrine markers.
Studies published on the long-acting form containing DAC showed that in healthy adults there were prolonged changes in the concentrations of circulating GH and IGF-1. Other research looked at the preservation of pulsatile GH secretion after exposure to CJC-1295.
The information offered by these studies concerning the GHRH signalling system and the pharmacological properties of the DAC-containing compound is useful; it should not, however, be taken as direct pharmacokinetic evidence for those substances marked CJC-1295 without DAC.
When carrying out comparative research, it is necessary to keep the difference between the parent GHRH analogue, the DAC-containing CJC-1295 and the shorter-acting modified GHRH(1-29) analogues clearly in mind.
Receptor Expression and Experimental Context
Receptor expression may differ from one tissue and one experimental system to another.
The GHS receptor has been found in tissue from the pituitary and hypothalamus as well as in a number of peripheral tissues. Moreover, experimental studies have examined the expression of GHS receptors in connection with exposure to Hexarelin.
The signalling of the GHRH receptor is mainly linked with the pituitary somatotrophs, since GHRH exerts its effect by means of a class B GPCR to control the intracellular signalling related to the secretion of growth hormone.
The fact that receptors are found outside the main experimental tissue does not by itself prove that they have a physiological or therapeutic function; it only offers a basis for further investigation.
Because of this, receptor localisation studies should all be understood in light of receptor density, ligand concentration, downstream signalling and the experimental model employed.
Pharmacokinetic Differences Matter
Another important point of difference between these research compounds is their pharmacokinetics.
The published CJC-1295 molecule with DAC was specifically designed to alter peptide persistence through albumin association. Human studies of this compound reported a substantially prolonged circulating profile.
Since shorter analogues of GHRH do not have the albumin-binding modification that is responsible for the prolonged exposure seen with DAC-containing CJC-1295, their pharmacokinetic profile is different.
Hexarelin also has particular features with regard to its absorption, distribution, metabolism and clearance. It is these parameters which affect the relationship between receptor exposure and the biological endpoints that are measured.
As a result, it is possible for differences in exposure over time to be hidden when only one blood measurement is used to compare two peptides.
Analytical Identification of Peptide Variants
It is especially important to carry out analytical identification when looking at compounds that have the same commercial names but different structures.
Mass spectrometry helps verify molecular mass and peptide identity, while chromatographic methods provide data on purity and related species. It may be necessary to confirm the sequence when comparing closely related analogues or modified fragments.
The analytical record should specify the actual material that was tested rather than depending only on the product label provided by the supplier.
This is particularly relevant in the case of CJC-1295 terminology, since the molecule containing DAC and those marketed as CJC-1295 but without DAC can have significantly different chemical and pharmacokinetic properties.
Experimental Models Used in Published Research
Hexarelin has undergone investigation in cell systems, in pituitary preparations, in animal models and in human endocrine research. The experiments carried out have included receptor binding assays, gene-expression analysis, endocrine measurements and pharmacological challenge studies.
GHRH analogues have also been studied in pituitary cell systems, in animal models and in human endocrine studies. Research into CJC-1295 has involved receptor activity, pharmacokinetics, hormone measurements and analytical detection.
These models answer different questions.
A receptor-binding experiment is capable of showing a ligand-receptor interaction. A cell-based assay can be used to investigate intracellular signalling. An animal model can give information on integrated endocrine physiology. Human studies are able to measure circulating biomarkers under controlled conditions.
The evidence from one model should not be automatically applied to another.
Limitations of Current Research
One major limitation is terminology.
The term "CJC-1295" is often used on line without clearly specifying whether or not the substance in question contains the Drug Affinity Complex. This can make it hard to tell whether a published result refers to the precise compound under discussion.
Another limitation is that a great deal of the detailed pharmacology relates to the wider GHRH and growth hormone secretagogue systems rather than to the specific commercial product described by each supplier.
Another limitation relates to the interpretation of the end points. While changes in GH, IGF-1 or another circulating biomarker do indicate a measurable biological response under the conditions of the study, they do not prove that a clinical outcome has occurred.
In the end, the identity of the peptide, its purity, the confirmation of its sequence and the experimental conditions can all have a substantial effect on reproducibility, and research conclusions are most convincing when these factors are clearly recorded.
Research-Based Perspective
The example of hexarelin and CJC-1295 without DAC shows why peptide research should be based on molecular identity and receptor biology rather than on general outcome-based descriptions.
Hexarelin is part of the growth hormone secretagogue category and is linked to signalling through the GHS receptor. Research involving CJC-1295 relates to the GHRH signalling pathway, though the expression "CJC-1295 without DAC" needs a precise chemical definition since the most well-characterised literature on CJC-1295 refers to the analogue that contains DAC.
The areas of research may come together when it comes to the regulation of growth hormone, but their receptor systems, structures and pharmacokinetic properties are not the same.
A comparison that is most informative in the context of laboratory research should begin with confirmed peptide identity, the receptor target, the downstream signalling pathway, the exposure profile and the endpoint that has been experimentally measured.
Research Use Only
Direct SARMS are supplied for use in laboratory and analytical applications. The information given in this section is for scientific and educational purposes only.
They are not intended for use by humans in the form of food, for the purpose of diagnosing, treating, curing or preventing any disease or medical condition, and no dosage, method of administration or protocol for human use is given.
Before using any material, researchers should independently assess its identity, purity, analytical documentation, and experimental suitability.
If you want to find out more about compounds and information relating to peptides in the laboratory, please go to.
View research materialsFAQs
References
- Jetté L, Léger R, Thibaudeau K, Benquet C, Robitaille M, Pellerin I, Paradis V, van Wyk P, Pham K, Bridon DP. 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 Jul;146(7):3052-8. doi: 10.1210/en.2004-1286. Epub 2005 Apr 7. PubMed ↗
- 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. J Clin Endocrinol Metab. 2006 Mar;91(3):799-805. doi: 10.1210/jc.2005-1536. Epub 2005 Dec 13. PubMed ↗
- Ionescu M, Frohman LA. Pulsatile secretion of growth hormone (GH) persists during continuous stimulation by CJC-1295, a long-acting GH-releasing hormone analog. J Clin Endocrinol Metab. 2006 Dec;91(12):4792-7. doi: 10.1210/jc.2006-1702. Epub 2006 Oct 3. PubMed ↗
- Korbonits M, Kaltsas G, Perry LA, Putignano P, Grossman AB, Besser GM, Trainer PJ. The growth hormone secretagogue hexarelin stimulates the hypothalamo-pituitary-adrenal axis via arginine vasopressin. J Clin Endocrinol Metab. 1999 Jul;84(7):2489-95. doi: 10.1210/jcem.84.7.5811. PubMed ↗
- Korbonits M, Kaltsas G, Perry LA, Putignano P, Grossman AB, Besser GM, Trainer PJ. The growth hormone secretagogue hexarelin stimulates the hypothalamo-pituitary-adrenal axis via arginine vasopressin. J Clin Endocrinol Metab. 1999 Jul;84(7):2489-95. doi: 10.1210/jcem.84.7.5811. PubMed ↗
- Muccioli G, Ghè C, Ghigo MC, Papotti M, Arvat E, Boghen MF, Nilsson MH, Deghenghi R, Ong H, Ghigo E. Specific receptors for synthetic GH secretagogues in the human brain and pituitary gland. J Endocrinol. 1998 Apr;157(1):99-106. doi: 10.1677/joe.0.1570099. PubMed ↗
- Robberecht P, Coy DH, Waelbroeck M, Heiman ML, de Neef P, Camus JC, Christophe J. Structural requirements for the activation of rat anterior pituitary adenylate cyclase by growth hormone-releasing factor (GRF): discovery of (N-Ac-Tyr1, D-Arg2)-GRF(1-29)-NH2 as a GRF antagonist on membranes. Endocrinology. 1985 Nov;117(5):1759-64. doi: 10.1210/endo-117-5-1759. PubMed ↗
- SARMS for direct use. For research only - see peptide information and laboratory documentation.
