title: Morphine 6-glucuronide and morphine 3-glucuronide as molecular chameleons with unexpected lipophilicity.
abstract: Morphine 6-glucuronide, but not morphine 3-glucuronide, is a highly potent opiate receptor agonist. In fact, there is converging evidence that much of the analgesic effect occurring after morphine treatment in humans is due to this metabolite rather than to the parent drug. Yet glucuronides as a rule are considered as highly polar metabolites unable to cross the blood-brain barrier and rapidly excreted by the urinary and/or biliary routes. Here, we report that morphine 6-glucuronide, and to a lesser extent morphine 3-glucuronide, are far more lipophilic than predicted, and in fact not much less lipophilic than morphine itself. Force-field and quantum mechanical calculations indicate that the two glucuronides can exist in conformational equilibrium between extended and folded forms. The extended conformers, because they efficiently expose their polar groups, must be highly hydrophilic forms predominating in polar media such as water; in contrast, the folded conformers mask part of their polar groups, thus being more lipophilic and likely to predominate in media of low polarity such as biological membranes.
authors.affiliation: Institut de Chimie Thérapeutique, Ecole de Pharmacie, Université de Lausanne, Switzerland.
authors.forename: P A
authors.initials: PA
authors.lastname: Carrupt
authors.forename: B
authors.initials: B
authors.lastname: Testa
authors.forename: A
authors.initials: A
authors.lastname: Bechalany
authors.forename: N
authors.initials: N
authors.lastname: el Tayar
authors.forename: P
authors.initials: P
authors.lastname: Descas
authors.forename: D
authors.initials: D
authors.lastname: Perrissoud
mesh_terms: D002151:Calorimetry; D003196:Computer Graphics; D007202:Indicators and Reagents; D008958:Models, Molecular; D008968:Molecular Conformation; D009022:Morphine Derivatives / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D007202:Indicators and Reagents; D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; C018108:morphine-3-glucuronide