Chemical Identity

Property	Value
Name	Dynorphin A
Gene	PDYN (chromosome 20p13)
Sequence	Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr-Arg-Ser-Gln-Glu-Pro
Length	17 amino acids
N-terminal	YGGFL (shared with Leu-enkephalin)
MW	2147.5 Da
PDB Structures	2N2B (NMR in SDS micelles)

Prodynorphin Processing

Prodynorphin → Dynorphin A (17 aa) + Dynorphin B (13 aa) + α-neoendorphin (10 aa) + β-neoendorphin (9 aa)

Key Enzymes

• Prohormone convertases: PC1/3, PC2
• Carboxypeptidase E: C-terminal trimming
• Signal peptidase: N-terminal signal peptide removal

Receptor

Kappa-Opioid Receptor (KOR)

• Gene: OPRK1 (chromosome 8q11.2)
• G-protein: Gαi → ↓cAMP, ↑K⁺ conductance, ↓Ca²⁺ conductance
• Selectivity: Dynorphin A is the endogenous KOR ligand (Kd ~0.5 nM)

Opioid Receptor Comparison

Receptor	Endogenous Ligand	Primary Effects
Mu (MOR)	β-endorphin, enkephalins	Analgesia, euphoria, respiratory depression
Delta (DOR)	Enkephalins	Analgesia, mood, reward
Kappa (KOR)	Dynorphin A	Analgesia, dysphoria, diuresis

Physiological Functions

Pain Modulation

• Dynorphin A is the most potent endogenous opioid at KOR
• Acts in spinal cord dorsal horn to modulate nociception
• Paradox: Chronic dynorphin may cause hyperalgesia (pain sensitization)

Stress Response

• Released during stress in brain regions involved in fear and anxiety
• Dysphoria: KOR activation produces dysphoria (unlike MOR activation)
• Anxiety: Dynorphin in amygdala modulates anxiety-related behavior

Diuresis

• KOR activation inhibits ADH release
• Promotes water diuresis
• This is why dynorphin was originally called “dynorphin” (dynamic + morphine)

Other Functions

• Appetite: KOR modulation of feeding
• Addiction: KOR activation during withdrawal may contribute to dysphoria
• Neuroprotection: Some evidence for neuroprotective effects

Therapeutic Potential

KOR Agonists

Drug	Indication	Status
Salvinorin A	Research tool	Research
U-50488	Research tool	Research
CR847	Pain	Preclinical
CERC-501	Depression, addiction	Phase II

KOR Antagonists

Drug	Indication	Status
JDTic	Depression	Preclinical
CERC-501 (low dose)	Depression	Phase II

Manufacturing

• SPPS (Fmoc): Standard solid-phase synthesis
• Purification: RP-HPLC
• Characterization: Mass spectrometry, NMR

References

1. Cone EJ, et al. “Isolation and structure of dynorphin from human brain.” PNAS 80:4501-4505, 1983. doi:10.1073/pnas.80.14.4501
2. Chavkin C, et al. “Dynorphin is a specific endogenous ligand of the kappa opioid receptor.” Science 215:413-415, 1982.
3. Bruchas MR, et al. “The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors.” Brain Research 1314:44-55, 2010.
4. Pfeiffer A, et al. “Characterization of the kappa opioid receptor in human brain.” Journal of Neurochemistry 46:1016-1023, 1986.
5. Lutfy K, Bhatt DK. “Dynorphin and the pathophysiology of pain.” Neuropeptides 43:1-10, 2009.