1. Systemic analgesic activity and delta-opioid selectivity in [2,6-dimethyl-Tyr1,D-Pen2,D-Pen5]enkephalin.
- Author
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Hansen DW Jr, Stapelfeld A, Savage MA, Reichman M, Hammond DL, Haaseth RC, and Mosberg HI
- Subjects
- Analgesics chemical synthesis, Analgesics metabolism, Animals, Brain metabolism, Cell Membrane metabolism, Electric Stimulation, Enkephalins chemical synthesis, Enkephalins metabolism, Male, Mice, Mice, Inbred ICR, Muscle Contraction drug effects, Pain Measurement, Receptors, Opioid, delta, Receptors, Opioid, mu, Structure-Activity Relationship, Vas Deferens drug effects, Vas Deferens physiology, Analgesia, Analgesics pharmacology, Enkephalins pharmacology, Receptors, Opioid physiology
- Abstract
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.
- Published
- 1992
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