Synthesis, Conformation, and Biological Characterization of a Sugar Derivative of Morphine that is a Potent, Long-Lasting, and Nontolerant Antinociceptive

• Published in: Journal of medicinal chemistry 2009-05, Vol.52 (9), p.2656-2666
• Main Authors: Arsequell, Gemma, Salvatella, Mariona, Valencia, Gregorio, Fernández-Mayoralas, Alfonso, Fontanella, Marco, Venturi, Chiara, Jiménez-Barbero, Jesús, Marrón, Ezequiel, Rodríguez, Raquel E
• Format: Article
• Language: English
• Subjects: Analgesics; Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - metabolism; Analgesics - pharmacology; Animals; Biological and medical sciences; Cell Line; Drug Tolerance; Male; Mannosides - chemical synthesis; Mannosides - chemistry; Mannosides - metabolism; Mannosides - pharmacology; Medical sciences; Models, Molecular; Molecular Conformation; Morphine - chemical synthesis; Morphine - chemistry; Morphine - metabolism; Morphine - pharmacology; Morphine Derivatives - chemical synthesis; Morphine Derivatives - chemistry; Morphine Derivatives - metabolism; Morphine Derivatives - pharmacology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu - metabolism; Time Factors
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm8011245

A synthetic mannoside derivative, namely, 6-morphinyl-α-d-mannopyranoside, shows a naloxone-reversible antinociception that is 100-fold more potent and twice as long lasting compared to morphine when administered intraperitoneally to rats in paw pressure and tail flick tests. The compound does not produce tolerance and binds to rat μ opioid receptors with twice the affinity of morphine. NMR studies suggest that differences of activity between the derivative and its parent compound M6G might be related to their differing molecular dynamic behavior.