Systemic analgesic activity and .delta.-opioid selectivity in [2,6-dimethyl-Tyr1, D-Pen2, D-Pen5]enkephalin

The cyclic peptide [2,6-dimethyl-Tyr1,D-Pen2,D-Pen5]enkephalin (2) was synthesized by solid-phase techniques and contains the optically pure unnatural amino acid 2,6-dimethyltyrosine (DMT) as a replacement for the Tyr1 residue of [D-Pen2,D-Pen5]enkephalin (DPDPE, 1). This structural modification res...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1992-02, Vol.35 (4), p.684-687
Main Authors: Hansen, Donald W, Stapelfeld, Awilda, Savage, Michael A, Reichman, Melvin, Hammond, Donna L, Haaseth, Ronald C, Mosberg, Henry I
Format: Article
Language:English
Subjects:
Analgesia
Analgesics - chemical synthesis
Analgesics - metabolism
Analgesics - pharmacology
Animals
Brain - metabolism
Cell Membrane - metabolism
Chemistry
Electric Stimulation
Enkephalins - chemical synthesis
Enkephalins - metabolism
Enkephalins - pharmacology
Exact sciences and technology
Male
Mice
Mice, Inbred ICR
Muscle Contraction - drug effects
Organic chemistry
Pain Measurement
Peptides
Preparations and properties
Receptors, Opioid - physiology
Receptors, Opioid, delta
Receptors, Opioid, mu
Structure-Activity Relationship
Vas Deferens - drug effects
Vas Deferens - physiology
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Summary:The cyclic peptide [2,6-dimethyl-Tyr1,D-Pen2,D-Pen5]enkephalin (2) was synthesized by solid-phase techniques and contains the optically pure unnatural amino acid 2,6-dimethyltyrosine (DMT) as a replacement for the Tyr1 residue of [D-Pen2,D-Pen5]enkephalin (DPDPE, 1). This structural modification resulted in a 10-fold increase in the potency of 2 at the delta opioid receptor and a 35-fold increase in potency at the mu receptor while substantial delta receptor selectivity was maintained. In addition, 2 was 86-fold more effective than 1 at inhibiting electrically stimulated contractions of the mouse vas deferens. In the hot plate test, 2 was 7-fold more potent than 1 after intracerebroventricular administration in the mouse. While 1 was inactive following systemic administration of doses as high as 30 mg/kg, subcutaneous administration of 2 significantly inhibited writhing with an ED50 of 2.6 mg/kg. These results demonstrate that the potency and systemic activity of DPDPE are significantly increased by replacement of Tyr1 with DMT.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00082a008