Design, Chemical Synthesis, and Biological Evaluation of Thiosaccharide Analogues of Morphine- and Codeine-6-Glucuronide

• Published in: Journal of medicinal chemistry Vol. 47; no. 23; pp. 5809 - 5815
• Main Authors: MacDougall, James M, Zhang, Xiao-Dong, Polgar, Willma E, Khroyan, Taline V, Toll, Lawrence, Cashman, John R
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 04.11.2004; Amer Chemical Soc
• Subjects: Analgesics; Analgesics, Opioid - chemical synthesis; Analgesics, Opioid - chemistry; Analgesics, Opioid - pharmacology; Animals; Binding, Competitive; Biological and medical sciences; Chemistry, Medicinal; Codeine - analogs & derivatives; Codeine - chemical synthesis; Codeine - chemistry; Codeine - pharmacology; Drug Design; Glycosides - chemical synthesis; Glycosides - chemistry; Glycosides - pharmacology; Life Sciences & Biomedicine; Male; Medical sciences; Mice; Mice, Inbred ICR; Morphine Derivatives - chemical synthesis; Morphine Derivatives - chemistry; Morphine Derivatives - pharmacology; Neuropharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Radioligand Assay; Receptors, Opioid, delta - drug effects; Receptors, Opioid, delta - metabolism; Receptors, Opioid, kappa - drug effects; Receptors, Opioid, kappa - metabolism; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - metabolism; Science & Technology; Structure-Activity Relationship; Sulfides - chemical synthesis; Sulfides - chemistry; Sulfides - pharmacology; MORPHINE; BINDING; AGONISTS; BRAIN; Partial agonist; Agonist; Morphine derivatives; Rodentia; μ Opioid receptor; Opiates; Narcotic analgesic; In vitro; In vivo; Vertebrata; Mammalia; Tail flick test; Structure activity relation; Mouse; Animal; Thioglycoside; Affinity; Subcutaneous administration; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049554t

A series of 6-β-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 μ, δ, and κ opioid receptors. The thiosaccharide compounds in the morphine series 5b, 5e, 6a, and 6c showed 1.5−2.4-fold higher affinity for the μ 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-γ-S assay. Compounds 5b and 5e were determined to be full μ agonists, whereas compounds 6a and 6c were partial μ 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.