Met-enkephalin
Met-enkephalin is an endogenous pentapeptide opioid that modulates pain perception and stress responses through delta-opioid receptor activation.
Chemical Identity
| Property | Value |
|---|---|
| Chemical Formula | C27H35N5O7S |
| Molecular Weight | 573.66 g/mol |
| CAS Number | 58569-55-4 |
| IUPAC Name | Tyr-Gly-Gly-Phe-Met |
| Peptide Class | Endogenous Opioid Peptide |
| Sequence Homology | Identical to endogenous Met-enkephalin |
Structure
Met-enkephalin (Tyr-Gly-Gly-Phe-Met) is a pentapeptide and one of the endogenous opioid peptides discovered in 1975 by Hughes, Smith, and Kosterlitz. It differs from Leu-enkephalin only at the C-terminal position (methionine vs. leucine). Met-enkephalin is derived from proenkephalin (proenkephalin A), which contains seven copies of the Met-enkephalin sequence and one copy of Leu-enkephalin. The N-terminal Tyr-Gly-Gly-Phe motif is shared across all opioid peptides and is essential for receptor binding.
Mechanism of Action
Met-enkephalin preferentially binds to delta-opioid receptors (DOR), with moderate affinity for mu-opioid receptors. Activation of delta-opioid receptors produces:
- Analgesia: Spinal and supraspinal pain modulation
- Cardioprotection: Protection against ischemia-reperfusion injury
- Neuroprotection: Reduced excitotoxicity and neuroinflammation
- Mood regulation: Anxiolytic and antidepressant-like effects
Signal transduction occurs through Gi/o-protein coupling, inhibiting adenylyl cyclase, activating inwardly rectifying potassium channels, and inhibiting voltage-gated calcium channels.
Biological Functions
Met-enkephalin serves as an endogenous modulator of pain perception in the periaqueductal gray, dorsal horn, and peripheral nociceptors. It is released alongside other neurotransmitters from interneurons in the spinal cord, where it presynaptically inhibits pain signal transmission. Met-enkephalin also modulates stress responses, immune function, and gastrointestinal motility.
Pharmacokinetics
- Half-life: 2-5 minutes (plasma)
- Degradation: Rapid cleavage by enkephalinases (NEP, aminopeptidase N)
- BBB penetration: Limited due to polar structure
- Stability: Requires synthetic modifications for therapeutic use
The short half-life of native Met-enkephalin has driven development of protease-resistant analogs and enzyme inhibitors (e.g., thiorphan, racecadotril) to enhance endogenous enkephalin signaling.
Clinical Relevance
While Met-enkephalin itself is not used clinically due to rapid degradation, its derivatives and approaches targeting the enkephalinergic system are under investigation. Racecadotril (acetorphan), an enkephalinase inhibitor, is approved in many countries for acute diarrhea. Deltorphin and DADLE analogs are in preclinical development for pain and cardioprotection.
References
- Hughes, J., et al. (1975). Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature, 258, 577-579.
- Roques, B.P., et al. (1993). The enkephalinase inhibitor thiorphan shows antinociceptive activity in mice. Nature, 288, 286-288.
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