CJC-1295 No Dac: Mechanism of Action

Mechanism of Action

CJC-1295 (no DAC) functions as a selective GHRH receptor agonist that binds to growth hormone-releasing hormone receptors (GHRHr) on somatotroph cells in the anterior pituitary gland, initiating a cAMP-dependent signaling cascade that stimulates growth hormone (GH) gene transcription, synthesis, and pulsatile secretion.[7][8]

Primary Receptor Target & Binding Characteristics

Property	Detail	Evidence
Primary Target	Growth Hormone-Releasing Hormone Receptor (GHRHr) on anterior pituitary somatotrophs	Teichman et al. (2006); Alba et al. (2006)[8]
Receptor Class	Class B1 (secretin family) G protein-coupled receptor (GPCR)	Established GHRH receptor pharmacology[7]
Binding Affinity	High affinity; mimics native GHRH structure with enhanced stability from tetrasubstitution	Jetté et al. (2005)[4]
Binding Reversibility	Reversible binding; crucial for maintaining physiological balance and preventing GH axis overstimulation	Pharmacokinetic profile[5]
Half-Life	~30 minutes (vs. minutes for native GHRH; vs. 6–8 days for CJC-1295 with DAC)	Soule et al. (1994); Henninge et al. (2010)[2][1]
Selectivity	Highly selective for GHRHr on pituitary somatotrophs; possible low-level cross-reactivity within the secretin receptor family	86% homology with endogenous GHRH[7]
DPP-4 Resistance	D-Alanine at position 2 prevents dipeptidyl peptidase-4 cleavage that rapidly degrades native GHRH	Jetté et al. (2005); Soule et al. (1994)[4][2]

Downstream Signaling Cascade

Step	Event	Molecular Detail
1. Receptor Binding	CJC-1295 (no DAC) binds GHRHr on somatotroph cell surface	High-affinity, reversible "lock-and-key" interaction mimicking native GHRH[7]
2. G-Protein Activation	Ligand-receptor interaction activates stimulatory G-proteins (Gs)	Gsα subunit dissociates and activates downstream effectors[7]
3. cAMP Production	Gs activates adenylyl cyclase; ATP is converted to cyclic AMP (cAMP)	Intracellular cAMP levels increase significantly (dose-dependent)[7][14]
4. PKA Activation	Elevated cAMP activates Protein Kinase A (PKA) phosphorylation cascades	PKA phosphorylates transcription factors including CREB[7]
5. GH Gene Transcription	PKA cascade stimulates GH gene transcription and protein synthesis in somatotrophs	Increased GH mRNA and total pituitary RNA[7][8]
6. Pulsatile GH Secretion	GH is released in a physiological pulse from anterior pituitary	~30 min half-life produces pulsatile (not continuous) GH release[5][6]
7. IGF-1 Stimulation	Released GH stimulates the liver to produce Insulin-like Growth Factor-1 (IGF-1)	GH/IGF-1 axis activation drives downstream anabolic effects[8]

Alternative Signaling Pathways

While the G_s/cAMP/PKA cascade is the primary signaling pathway, CJC-1295 (no DAC) may also engage the MAPK (mitogen-activated protein kinase) and PI3K/Akt pathways, which contribute to anabolic effects (protein synthesis via mTOR), anti-apoptotic signaling, and cellular proliferation.[7]

Cellular and Tissue-Level Effects

Effect	Detail	Evidence
Somatotroph Proliferation	Stimulates proliferation of pituitary somatotroph cells; increases total pituitary RNA and GH mRNA	Alba et al. (2006) (DAC variant)[8]
GH/IGF-1 Axis	Stimulates pulsatile GH release; liver produces IGF-1; dose-dependent GH and IGF-1 elevation	Teichman et al. (2006) (DAC variant)[8]
Lipolysis	GH promotes fat breakdown via hormone-sensitive lipase activation; inhibits lipogenesis	GH/IGF-1 axis pharmacology[7]
Protein Synthesis	Enhances muscle protein synthesis via mTOR pathway activation downstream of GH/IGF-1	GH secretagogue literature[12]
Tissue Repair	Accelerates wound healing and connective tissue repair through collagen synthesis stimulation	GH/IGF-1 axis regenerative properties[12]
DNA Damage (Pituitary)	Intense cAMP stimulation by CJC-1295 in mouse pituitary cells induced DNA damage (H2AX phosphorylation and comet assays)	Ben-Shlomo et al. (2020) (likely DAC variant)[14]

Comparison: CJC-1295 No DAC vs. Related Compounds

Parameter	CJC-1295 No DAC (Mod GRF 1-29)	CJC-1295 With DAC	Native GHRH(1-29) / Sermorelin
Half-Life	~30 minutes	6–8 days	Minutes
GH Release Pattern	Pulsatile (physiological)	Continuous (non-physiological)	Pulsatile (very brief)
DPP-4 Resistance	Yes (D-Ala² substitution)	Yes (D-Ala² substitution)	No (rapidly cleaved)
Albumin Binding	None	Covalent (via MPA-Lys linker)	None
Receptor Desensitization Risk	Low (pulsatile clearance)	Higher (chronic stimulation)	Low (too brief to cause)
Clinical Trials	None identified for this specific compound	Phase I/II completed (Teichman 2006; Ionescu 2006)	FDA-approved (as Sermorelin, discontinued)