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Published on: July 29, 2014
Morphine-6beta-glucuronide and morphine-3-glucuronide, opioid receptor agonists with different potencies
1University of Leuven, Faculty of Pharmaceutical Sciences, Laboratory of Toxicology, Van Evenstraat 4, 3000, Leuven, Belgium.
Biochemical Pharmacology
|November 14, 2001
Summary
Morphine-6beta-glucuronide (M6G) and morphine-3-glucuronide (M3G) are opioid receptor agonists with varying potencies. Specific mutations in the human mu-opioid receptor (hMOR) alter the potency of morphinan ligands.
Area of Science:
- Pharmacology
- Neuroscience
- Molecular Biology
Background:
- Opioid receptors (mu, kappa, delta) mediate the effects of analgesics like morphine.
- Morphine metabolites, morphine-6beta-glucuronide (M6G) and morphine-3-glucuronide (M3G), have distinct pharmacological profiles.
- Understanding the structure-activity relationships of opioid ligands is crucial for developing targeted therapeutics.
Purpose of the Study:
- To compare the potencies of morphine, M6G, and M3G at cloned human mu-, kappa-, and delta-opioid receptors (hMOR, hKOR, hDOR).
- To investigate the role of specific residues (Trp318, His319) in the hMOR for the selectivity of morphinan alkaloids.
- To elucidate the molecular basis for differential receptor interactions of opioid ligands.
Main Methods:
- Heterologous expression of human opioid receptors (hMOR, hKOR, hDOR) in Xenopus laevis oocytes.
- Co-expression with G-protein coupled inwardly rectifying K(+) (GIRK) channels (GIRK1/GIRK2) and RGS4.
- Two-microelectrode voltage clamp technique to measure receptor-activated channel currents; site-directed mutagenesis of hMOR.
Main Results:
- M6G exhibited higher potency at hMOR, lower at hKOR, and similar at hDOR compared to morphine.
- M3G demonstrated significantly lower and non-selective potency across opioid receptors.
- Single point mutation (W318L) on hMOR conferred delta-like potency for morphine and M6G; double mutation (W318Y/H319Y) partially conferred kappa-like potency.
Conclusions:
- Both M6G and M3G act as opioid receptor agonists with distinct potencies.
- The potency of morphinan ligands is significantly influenced by specific amino acid residues within the hMOR.
- Trp318 and His319 in hMOR are critical determinants of selectivity for morphinan alkaloids.
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