Abstract
To synthesize potent antagonists of the mu-opioid receptor, we prepared a series of endomorphin-1 and endomorphin-2 analogues with 3-(1-naphthyl)-d-alanine (d-1-Nal) or 3-(2-naphthyl)-d-alanine (d-2-Nal) in position 4. Some of these analogues displayed weak antagonist properties. We tried to strengthen these properties by introducing the structurally modified tyrosine residue 2,6-dimethyltyrosine (Dmt) in place of Tyr1. Among the synthesized compounds, [Dmt1, d-2-Nal4]endomorphin-1, designated antanal-1, and [Dmt1, d-2-Nal4]endomorphin-2, designated antanal-2, turned out to be highly potent and selective mu-opioid receptor antagonists, as judged on the basis of two functional assays, the receptor binding assay and the hot plate test of analgesia. Interestingly, another analogue of this series, [Dmt1, d-1-Nal4]endomorphin-1, turned out to be a moderately potent mixed mu-agonist/delta-antagonist.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aequorin
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Analgesics / chemical synthesis
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Analgesics / chemistry
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Analgesics / pharmacology
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Animals
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Binding Sites
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Brain / metabolism
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CHO Cells
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Calcium / metabolism
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Cricetinae
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Cricetulus
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Guinea Pigs
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Ileum / drug effects
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Ileum / physiology
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In Vitro Techniques
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Luminescent Agents
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Male
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Mice
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Muscle Contraction / drug effects
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Muscle, Smooth / drug effects
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Muscle, Smooth / physiology
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Oligopeptides / chemical synthesis*
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Oligopeptides / chemistry
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Oligopeptides / pharmacology
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Rats
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Receptors, Opioid, delta / antagonists & inhibitors
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Receptors, Opioid, mu / agonists
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Receptors, Opioid, mu / antagonists & inhibitors*
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Structure-Activity Relationship
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Vas Deferens / drug effects
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Vas Deferens / physiology
Substances
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Analgesics
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Luminescent Agents
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Oligopeptides
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Receptors, Opioid, delta
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Receptors, Opioid, mu
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endomorphin-1, Dmt(1)-2-Nal(4)-
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endomorphin-2, Dmt(1)-2-Nal(4)-
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Aequorin
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Calcium