title: Synthesis and in vitro biological evaluation of a carbon glycoside analogue of morphine-6-glucuronide.
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.
authors.affiliation: Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121-2804, USA. jmacdougall@hbri.org
authors.forename: James M
authors.initials: JM
authors.lastname: MacDougall
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhang
authors.forename: Willma E
authors.initials: WE
authors.lastname: Polgar
authors.forename: Taline V
authors.initials: TV
authors.lastname: Khroyan
authors.forename: Lawrence
authors.initials: L
authors.lastname: Toll
authors.forename: John R
authors.initials: JR
authors.lastname: Cashman
mesh_terms: D000818:Animals; D006027:Glycosides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D000882:Haplorhini; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D008956:Models, Chemical; D015394:Molecular Structure; D009022:Morphine Derivatives / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism
chemical_list: D006027:Glycosides; D009022:Morphine Derivatives; D011957:Receptors, Opioid; C035349:morphine-6-glucuronide