CJC-1295 (No DAC)

CJC-1295 (No DAC) is a synthetic analogue of human GHRH(1-29) incorporating four targeted amino acid modifications that confer DPP-IV resistance and improved chemical stability while fully preserving GHRHR agonist activity. Also widely designated Modified GRF 1-29 (Mod GRF 1-29), it is the most extensively used synthetic GHRH analogue in growth hormone axis research.

The four modifications relative to native Sermorelin (GHRH 1-29) address specific degradation vulnerabilities. D-Ala substitution at position 2 (replacing L-Ala2) provides complete DPP-IV resistance: DPP-IV requires a free N-terminal amine and an L-amino acid at position 2 for substrate recognition at the Ala2-Asp3 cleavage site — the D-configuration creates a stereochemical mismatch that prevents productive DPP-IV binding. This single modification extends half-life from Sermorelin's 10-20 minutes to approximately 30 minutes. Gln substitution at position 8 (replacing Asn8) prevents asparagine deamidation — a spontaneous chemical reaction (Asn→Asp) that alters peptide charge and receptor affinity, particularly at Asn-Gly sequences — improving long-term storage and solution stability. Ala substitution at position 15 (replacing Gly15) reduces backbone conformational flexibility, improving overall peptide stability. Leu substitution at position 27 (replacing Met27) eliminates methionine oxidative vulnerability, providing stability under oxidative assay conditions.

GHRHR is a class B GPCR (secretin receptor family, structurally related to receptors for glucagon, GLP-1, GIP, PTH, and VIP) that couples to Gs. CJC-1295 No DAC binding activates Gs, stimulating adenylyl cyclase (primarily AC5/AC6 in pituitary somatotrophs) and raising intracellular cAMP. PKA activation phosphorylates CREB at Ser133, driving GH gene transcription through cAMP response elements. PKA also phosphorylates L-type voltage-gated calcium channels (Cav1.2/Cav1.3), increasing calcium influx that triggers GH secretory granule exocytosis through SNARE protein-dependent membrane fusion.

The combination of CJC-1295 No DAC with Ipamorelin represents the most widely used GH axis dual-receptor research paradigm. CJC-1295 No DAC activates GHRHR through the Gs/cAMP/PKA pathway, while Ipamorelin activates GHS-R1a through the Gq/11/IP3/calcium pathway. These mechanistically distinct intracellular cascades produce additive to synergistic GH release in published research, with Ipamorelin additionally suppressing hypothalamic somatostatin — the primary inhibitory brake on GH secretion — further amplifying GHRHR-mediated GH release.

Research comparing CJC-1295 No DAC with Sermorelin directly quantifies the DPP-IV resistance benefit: in serum-containing pituitary cell culture maintained for 4+ hours, Sermorelin undergoes approximately 50% degradation within 20 minutes, producing a rapidly declining effective concentration. CJC-1295 No DAC maintains more stable effective concentrations, enabling reproducible dose-response characterisation across extended incubation periods.

Cell line selection for GHRHR research: primary rat anterior pituitary cells are the gold standard; HEK293 cells stably expressing recombinant human GHRHR are appropriate for cAMP-based functional assays; GH3 rat pituitary adenoma cells have limited GHRHR expression but high GHS-R1a expression, making them appropriate for Ipamorelin but not CJC-1295 No DAC pharmacology.