morphinans and norbuprenorphine

Buprenorphine shows strong analgesic effects on moderate to severe pain. Although buprenorphine can be used more safely than other opioid analgesics, it has room for improvement in clinical utility. Investigation of compounds structurally related to buprenorphine should be an approach to obtain novel analgesics with safer and improved profiles compared to buprenorphine. In the course of our previous studies, we observed that derivatives obtained by cyclizing C-homomorphinans were structurally related to buprenorphine. Hence, we synthesized cyclized C-homomorphinan derivatives with various oxygen functionalities on the side chains and evaluated their in vitro pharmacological profiles for the opioid receptors. Among the tested compounds, methyl ketone 2a with an N-methyl group showed full agonistic activities for the μ and the δ receptors and partial agonistic activity for the κ receptor. These properties were similar to those of norbuprenorphine, a major metabolite of buprenorphine, which reportedly contributes to the antinociceptive effect of buprenorphine. From these results, we concluded that cyclized C-homomorphinan would be a possible lead compound to obtain novel analgesics with buprenorphine-like properties.

Topics: Analgesics, Opioid; Animals; Buprenorphine; CHO Cells; Cricetinae; Cricetulus; Cyclization; Humans; Kinetics; Molecular Conformation; Morphinans; Protein Binding; Receptors, Opioid; Recombinant Proteins

A 63Ni electron-capture gas chromatographic assay is described for buprenorphine, a potent narcotic agonist--antagonist. In addition, the assay is useful for the measurement of the metabolite norbuprenorphine and demethoxybuprenorphine, a rearrangement product resulting when buprenorphine is exposed to acid and heat. An extraction procedure was developed which optimized recovery of buprenorphine from biological samples and produced minimal background interferences and emulsion problems. Extract residues were derivatized with pentafluoropropionic anhydride and assayed by gas chromatography. Samples were analyzed with and without enzyme hydrolysis, thus providing a selective and sensitive assay for both free and conjugated buprenorphine, norbuprenorphine and demethoxybuprenorphine. The lower limits of detection following extraction of a 1-ml sample were ca. 10 ng/ml for buprenorphine and demethoxybuprenorphine and 5 ng/ml for norbuprenorphine. Application of the assay to human samples following a 40-mg oral dose of buprenorphine produced no evidence for the presence of demethoxybuprenorphine in urine or feces. Norbuprenorphine (free and conjugated) was present in urinary and fecal samples; buprenorphine (free and conjugated) was found in high amounts only in feces and in trace amounts in urine as conjugated buprenorphine. The urinary and fecal excretion pattern observed for a human subject following oral dosing of buprenorphine suggests enterohepatic circulation of buprenorphine.

Topics: Adult; Body Fluids; Buprenorphine; Chromatography, Gas; Feces; Humans; Hydrolysis; Male; Middle Aged; Morphinans; Nickel; Radioisotopes; Time Factors

A selected-ion monitoring method was developed for determination of buprenorphine and its N-dealkylated metabolite (norbuprenorphine) in human plasma and urine. N-Propylnorbuprenorphine was added as internal standard to 2-3 ml of sample and the alkaloids were extracted with toluene-2 butanol at pH 9.4. After back-extraction in dilute sulphuric acid, the compounds were heated at 110 degrees C. This procedure led to quantitative loss of methanol followed by ring formation between the 6-methoxy group and the branched side-chain of all compounds. The derivatives were extracted into dichloromethane-2-butanol and treated with pentafluoropropionic anhydride. The resulting derivatives were suitable for selected-ion monitoring analysis. The coefficient of variation was found to be 4.5% at 5 ng/ml and 8.9% at 50 ng/ml in urine. The corresponding values for plasma were 6.2% and 5.3%, respectively. The lower limit of detection in plasma was 150 pg/ml, permitting analysis of plasma levels of buprenorphine for 24 h and urine levels of buprenorphine and norbuprenorphine for more than seven days after a therapeutic dose of buprenorphine. This method is the first with sufficient specificity and sensitivity for characterization of the clinical pharmacokinetics of buprenorphine.

Topics: Buprenorphine; Chemical Phenomena; Chemistry; Dealkylation; Humans; Hydrolysis; Morphinans; Time Factors