Practical and high-yield syntheses of dihydromorphine from tetrahydrothebaine and efficient syntheses of (8S)-8-bromomorphide.

A practical method for the conversion of tetrahydrothebaine to dihydromorphine in 92% yield is described. The procedure should allow more efficient production of opium products and may be easily modified for large-scale synthesis. The conversion of codeine to (8S)-8-bromomorphide, a potentially valuable intermediate to 6-demethoxyoripavine and derivatives, is also described. The absolute configuration of (8S)-8-bromomorphide was determined by a single-crystal X-ray diffraction study of the hydrobromide salt.

Postmortem distribution of dihydrocodeine and metabolites in a fatal case of dihydrocodeine intoxication.

A report of a fatal dihydrocodeine ingestion under substitution therapy is given. Quantitation of dihydrocodeine, dihydromorphine, N-nordihydrocodeine, dihydrocodeine-6-, dihydromorphine-6- and dihydromorphine-3-glucuronide was performed simultaneously after solid-phase extraction prior to HPLC analysis, and the analytes were detected using their native fluorescence. Postmortem concentrations of blood samples from different sampling sites as well as from liver, kidney and cerebrum are reported. A hair sample was investigated to prove long-term use of the substitute drug. Site-to-site differences of the analytes from blood samples were very small. The partition behavior of the opioid glucuronides depended on the hematocrit value of the particular blood sample. Most important findings seemed that dihydromorphine and dihydromorphine-6-glucuronide concentrations decisively contributed to the toxicity of dihydrocodeine. This case report outlines that in dihydrocodeine related deaths the concentrations of the pharmacologically active metabolites should additionally be determined for reliable interpretation.

Determination of the dihydrocodeine metabolites, dihydromorphine and nordihydrocodeine, in hepatic microsomal incubations by high-performance liquid chromatography.

A high-performance liquid chromatographic assay for the oxidative metabolites of dihydrocodeine, nordihydrocodeine and dihydromorphine, formed in human liver microsomal incubations, is described. A simple solvent extraction followed by reversed-phase high-performance liquid chromatography with UV detection allows quantification of both metabolites in a single assay. Standard curve concentration ranges for dihydromorphine and nordihydrocodeine were 0.05-5 and 0.2-20 microM, respectively. Assay performance was assessed by intra- and inter-day accuracy and precision of quality control (QC) samples. The difference between the calculated and the actual concentration and the relative standard deviation were less than 15% at low QC concentrations and less than 10% at medium and high QC concentrations for both analytes. The method provides good precision, accuracy and sensitivity for use in kinetic studies of the oxidative metabolism of dihydrocodeine in human liver microsomes.

Effects of nitrous oxide and halothane on mu and kappa opioid receptors in guinea-pig brain.

The effects of two general anesthetics, nitrous oxide and halothane, and oxygen on mu and kappa opioid receptor subtypes from guinea-pig brain were investigated. mu receptor binding was defined using [3H]dihydromorphine as the ligand. Nitrous oxide (100%) and halothane (2%) decreased the [3H]dihydromorphine binding affinity (Kdair = 0.87 nM, KdN2O = 1.45 nM, Kdhalothane = 2.30 nM) without affecting the density of binding sites. A decrease in the [3H]dihydromorphine binding affinity without influence on the density of binding sites was also observed in the presence of 100% oxygen (KdO2 = 1.40 nM). kappa receptor binding was defined using [3H](-)ethylketocyclazocine as the ligand, in the presence of 100 nM D-ala2-D-leu5-enkephalin and 30 nM morphine. While 100% nitrous oxide caused a slight decrease in [3H](-)ethylketocyclazocine binding affinity (Kdair = 0.24 nM, KdN2O = 0.31 nM) and a substantial decrease in the density of binding sites (Bmaxair = 115 fmol/mg protein, BmaxN2O = 84 fmol/mg protein), halothane dramatically affected both the affinity (Kdhalothane = 0.70 nM) and density (Bmaxhalothane = 38 fmol/mg protein). Oxygen (100%) reduced [3H]dihydromorphine binding affinity. Differential effects of two anesthetics on the same receptor or distinct actions of the same anesthetic on different receptors could indicate the presence of specific targets for anesthetics at the membrane level. Conversely, effects of volatile anesthetics on opioid receptors could reflect a non-specific perturbation of the lipidic and proteinaceous components of the membranes.