Synthesis and in vitro biological evaluation of a carbon glycoside analogue of morphine-6-glucuronide

Bioorg Med Chem Lett. 2005 Mar 15;15(6):1583-6. doi: 10.1016/j.bmcl.2005.01.072.

Abstract

Attachment of a glucose moiety to 6-beta-aminomorphine afforded compound 3, where the glucose moiety was linked to the C-6 nitrogen atom by a two-carbon bridge. The synthesis of 3 was accomplished in eight steps from 3-triisopropylsilyl-6-beta-aminomorphine and 2,3,4,6-tetra-O-benzyl-D-glucose. The C-glycoside 3 was prepared with the objective of examining a metabolically stable analogue of morphine-6-glucuronide and determining the potency and selectivity of opioid receptor binding. Competition binding assays showed that 3 bound to the mu opioid receptor with a Ki value of 3.5 nM. The C-glycoside 3 exhibited delta/mu and kappa/mu selectivity ratios of 76 and 165, respectively. The synthetic intermediate (i.e., benzyl precursor, compound 11) bound to the mu opioid receptor with a Ki value of 0.5 nM, was less selective for the mu opioid receptor. The [35S]GTPgammaS assay was used to evaluate the functional properties of compounds 3 and 11. Compound 3 was determined to be a full agonist at the mu opioid receptor, whereas compound 11 was found to be a partial agonist. Compound 3 was determined to be very stable in the presence of human liver S9, and rat and monkey liver microsomes: no detectable loss of 3 was observed up to 90 min. Compound 3 was also very stable at pH 2 and pH 7.4, suggesting that 3 possessed properties for sustained duration of action.

MeSH terms

  • Animals
  • Glycosides / chemical synthesis*
  • Glycosides / metabolism
  • Glycosides / pharmacology*
  • Haplorhini
  • In Vitro Techniques
  • Microsomes, Liver / metabolism
  • Models, Chemical
  • Molecular Structure
  • Morphine Derivatives / chemistry*
  • Morphine Derivatives / metabolism
  • Morphine Derivatives / pharmacology*
  • Rats
  • Receptors, Opioid / drug effects
  • Receptors, Opioid / metabolism

Substances

  • Glycosides
  • Morphine Derivatives
  • Receptors, Opioid
  • morphine-6-glucuronide