Chemical Identity

Property	Value
Name	Leucine-enkephalin
Gene	PENK (proenkephalin, chromosome 20pter-p12)
Sequence	Tyr-Gly-Gly-Phe-Leu
Abbreviation	YGGFL
Length	5 amino acids
Chemical Formula	C₂₈H₃₇N₅O₇
MW	555.6 Da
N-terminal	Tyrosine (essential for opioid activity)
PDB Structures	1PLW (NMR), 2LEU (NMR)

Discovery

Leucine-enkephalin was discovered by Kosterlitz and Hughes in 1975 as one of the first endogenous opioid peptides, demonstrating that the body produces its own morphine-like substances.

Nobel Prize 2004: Kosterlitz and John received the Nobel Prize for their discovery of enkephalins and opioid receptors.

Proenkephalin Processing

Proenkephalin (267 aa)
    → Enkephalin hexapeptides (4 copies of Met-enkephalin)
    → Enkephalin pentapeptides (1 copy of Leu-enkephalin)
    → Bovine adrenal medullary peptide (BAM)
    → Chromogranin A

Receptors

Delta-Opioid Receptor (DOR)

• Gene: OPRD1 (chromosome 1p36.1)
• G-protein: Gαi → ↓cAMP, ↑K⁺ conductance
• Selectivity: Leu-enkephalin has ~300× preference for DOR over MOR
• Distribution: Brain (cortex, hippocampus, amygdala), spinal cord

Other Opioid Receptors

Receptor	Leu-Enkephalin Affinity	Primary Ligand
Mu (MOR)	Moderate	β-endorphin
Delta (DOR)	High (preferred)	Enkephalins
Kappa (KOR)	Low	Dynorphin

Physiological Functions

Pain Modulation

• Analgesic: Activates DOR in spinal cord and brain
• Mechanism: ↓cAMP, ↑K⁺ conductance, ↓Ca²⁺ conductance
• Duration: Short (t½ ~2-3 min) due to rapid degradation

Mood and Reward

• Euphoria: DOR activation produces mild euphoria
• Anxiolysis: Reduces anxiety-related behaviors
• Antidepressant: DOR agonists show antidepressant effects

Other Functions

• GI motility: Modulates intestinal peristalsis
• Immune: Modulates immune cell function
• Cognition: Affects learning and memory

Clinical Significance

DOR Agonists

Drug	Indication	Status
SNC80	Depression	Preclinical
BW373U86	Pain, depression	Preclinical
AR-M17970	Pain	Research

Enkephalinase Inhibitors

Drug	Mechanism	Indication
Racecadotril	Inhibits enkephalin degradation	Diarrhea
Thiorphan	Inhibits neutral endopeptidase	Research

Manufacturing

• SPPS (Fmoc): Standard solid-phase synthesis
• Purification: RP-HPLC
• Characterization: Mass spectrometry
• Short t½: Requires modified analogs for clinical use

References

1. Hughes J, et al. “Identification of two pentapeptides from the brain with potent opiate agonist activity.” Brain Research 88:295-308, 1975. doi:10.1016/0006-8993(75)90411-6
2. Kosterlitz HW, Hughes J. “Development of the concepts of opiate receptors and their ligands.” Neuropharmacology 18:219-223, 1979.
3. Zadina JE, et al. “Endogenous opioids and pain.” Pain 136:1-15, 2008.
4. Pradhan AA, et al. “Toward the development of delta opioid receptor therapeutics.” Annals of the New York Academy of Sciences 1186:118-132, 2007.
5. Kieffer BL. “Delta-opioid receptors.” Cell 78:17-23, 1994.