Design, chemical synthesis, and biological evaluation of thiosaccharide analogues of morphine- and codeine-6-glucuronide.
A series of 6-beta-thiosaccharide analogues of morphine-6-glucuronide (M6G) and codeine-6-glucuronide (C6G) were synthesized and evaluated with the objective of preparing an analogue of M6G with improved biological activity. The affinity of the thiosaccharide analogues of M6G and C6G was examined by competitive binding assays at mu, delta, and kappa opioid receptors. The thiosaccharide compounds in the morphine series 5b, 5e, 6a, and 6c showed 1.5-2.4-fold higher affinity for the mu receptor than M6G, but were generally less selective than M6G. The functional activity of the M6G and C6G analogues was examined with the [35S]GTP-gamma-S assay. Compounds 5b and 5e were determined to be full mu agonists, whereas compounds 6a and 6c were partial mu agonists. The in vivo antinociceptive activity of compound 5b was evaluated by the tail flick latency test, giving an ED50 of 2.5 mg/kg.
MacDougall
James M
JM
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, California 92121-2804, USA.
Zhang
Xiao-Dong
XD
Polgar
Willma E
WE
Khroyan
Taline V
TV
Toll
Lawrence
L
Cashman
John R
JR
D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D003061:Codeine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006027:Glycosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009022:Morphine Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000187:drug effects / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000187:drug effects / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000701:Analgesics, Opioid; D006027:Glycosides; D009022:Morphine Derivatives; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013440:Sulfides; C035349:morphine-6-glucuronide; C061773:codeine-6-glucuronide; D003061:Codeine