Systemic analgesic activity and .delta.-opioid selectivity in [2,6-dimethyl-Tyr1, D-Pen2, D-Pen5]enkephalin
| Autor: | Donald W. Hansen, M A Savage, Melvin Reichman, Ronald C. Haaseth, Donna L. Hammond, Henry I. Mosberg, Awilda Stapelfeld |
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| Rok vydání: | 1992 |
| Předmět: |
Male
medicine.medical_specialty Enkephalin Receptors Opioid mu δ-opioid receptor Mice Structure-Activity Relationship Vas Deferens Receptors Opioid delta Internal medicine Drug Discovery medicine Animals Potency Hot plate test Pain Measurement Analgesics Mice Inbred ICR Chemistry Cell Membrane Brain Biological activity Enkephalins Electric Stimulation Endocrinology Opioid Receptors Opioid Systemic administration Molecular Medicine Analgesia μ-opioid receptor Muscle Contraction medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 35:684-687 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00082a008 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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