dextromethorphan and dimemorfan

Dimemorfan (DF) has been known to possess neuroprotective properties. While this promising compound deserves further biological evaluation, synthetic methods have not improved since Murakami group unveiled the synthetic efforts in 1972. Herein a succinct synthesis toward DF from commercially available 3-hydroxymorphinan (3-HM) is disclosed. Other morphinan analogs have been effectively prepared by adopting the similar methodology.

Topics: Dextromethorphan; Morphinans; Neuroprotective Agents

In a previous study, we demonstrated that a dextromethorphan analog, dimemorfan, has neuroprotective effects. Dextromethorphan and dimemorfan are high-affinity ligands at sigma1 receptors. Dextromethorphan has moderate affinities for phencyclidine sites, while dimemorfan has very low affinities for such sites, suggesting that these sites are not essential for the anticonvulsant actions of dimemorfan. Kainate (KA) administration (10 mg kg(-1), i.p.) produced robust convulsions lasting 4-6 h in rats. Pre-treatment with dimemorfan (12 or 24 mg kg(-1)) reduced seizures in a dose-dependent manner. Dimemorfan pre-treatment also attenuated the KA-induced increases in c-fos/c-jun expression, activator protein (AP)-1 DNA-binding activity, and loss of cells in the CA1 and CA3 fields of the hippocampus. These effects of dimemorfan were comparable to those of dextromethorphan. The anticonvulsant action of dextromethorphan or dimemorfan was significantly counteracted by a selective sigma1 receptor antagonist BD 1047, suggesting that the anticonvulsant action of dextromethorphan or dimemorfan is, at least in part, related to sigma1 receptor-activated modulation of AP-1 transcription factors. We asked whether dimemorfan produces the behavioral side effects seen with dextromethorphan or dextrorphan (a phencyclidine-like metabolite of dextromethorphan). Conditioned place preference and circling behaviors were significantly increased in mice treated with phencyclidine, dextrorphan or dextromethorphan, while mice treated with dimemorfan showed no behavioral side effects. Our results suggest that dimemorfan is equipotent to dextromethorphan in preventing KA-induced seizures, while it may lack behavioral effects, such as psychotomimetic reactions.

Topics: Animals; Dextromethorphan; Kainic Acid; Male; Mice; Mice, Inbred C57BL; Morphinans; Rats; Rats, Sprague-Dawley; Receptors, sigma; Seizures

Dextromethorphan ((+)-3-methoxy-N-methylmorphinan, DM) has been shown to have both anticonvulsant and neuroprotective effects. The mechanisms of these CNS effects of DM have been suggested to be associated with the low-affinity, noncompetitive, N-methyl-d-aspartate (NMDA) antagonism of DM and/or the high-affinity DM/sigma receptors. DM is largely O-demethylated into the phencyclidine (PCP)-like compound dextrorphan (DR), which may limit its therapeutic use by producing PCP-like adverse effects, such as hyperlocomotion. Dimemorfan ((+)-3-methyl-N-methylmorphinan, DF), an analog of DM, which has been safely used as an antitussive for more than 20 years, is also known not to form DR. This study therefore characterized the binding of DF to the sigma receptors and NMDA-linked PCP sites and examined the anticonvulsant as well as locomotor effects of DF in mice in comparison with those of DM and DR. We found that DF, DM, and DR were relative high-affinity ligands at sigma-1 receptors (Ki=151, 205, 144 nM, respectively) while all of them were with low affinity at sigma-2 receptors (Ki=4-11 microM). Only DR exhibited moderate affinity for PCP sites (Ki=0.9 microM), whereas DF (Ki=17 microM) and DM (Ki=7 microM) were much less active. DF, DM and DR produced prominent anticonvulsant effects in mice as measured by the supramaximal electroshock test with comparable potency (ED50 approximately 70 micromol/kg, i.p.). At the tested doses (20-260 micromol/kg, i.p.), DM and DR exhibited biphasic effects on the locomotor activity whereas DF produced a consistent dose-dependent decrease. These results revealed that, unlike DM and DR, DF did not cause a PCP-like hyperlocomotion adverse effect that is parallel with the PCP sites binding data. Furthermore, since they have equipotent anticonvulsant effects and similar binding affinities to sigma-1 receptors, the very low affinity of DF at PCP sites may suggest that acting on the PCP sites may not be the requisite for mediating the anticonvulsant activity of these DM analogs. With the history of safety and relative less adverse effects, DF appears to be worth further studying on its CNS effects other than the antitussive effect.

Topics: Animals; Anticonvulsants; Antitussive Agents; Behavior, Animal; Dextromethorphan; Dextrorphan; Dose-Response Relationship, Drug; Electroshock; Locomotion; Male; Mice; Morphinans; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, Phencyclidine; Receptors, sigma; Sigma-1 Receptor

Ion-selective electrodes (ISEs) responsive to the antitussives dextromethorphan and dimemorfan were constructed by the fixation of an ion-exchanger, ammonium tetraphenylborate, on a Millipore membrane by means of a plasma-polymerization technique. The electrodes showed a Nernstian response over the range of 10(-5)-10(-2) M dextromethorphan and dimemorphan, and the working pH range was 5-7. The interference from common cations such as Na+, K+ and Ca2+ was negligible but some organic cations interfered weakly. The electrodes were applied successfully for the determination of the drugs in pharmaceutical preparations.

Topics: Dextromethorphan; Electrodes; Levorphanol; Membrane Potentials; Morphinans

Topics: Animals; Antineoplastic Agents; Antitussive Agents; Carcinoma, Ehrlich Tumor; Dextromethorphan; Female; Levorphanol; Lipid Metabolism; Mice; Mice, Inbred Strains; Morphinans; Neoplasms, Experimental; Sarcoma 180

Dextromethorphan, dimemorfan, dihydrocodeine and oxymethebanol, centrally acting antitussives, were examined for their effect on Ehrlich carcinoma cells and sarcoma-180 cells in vitro or in vivo. The tumor cells were suspended in Hanks balanced salt solution (pH 7.4) supplemented with 2% bovine albumin, and they were incubated with and without 1 mM drugs at 37 degrees C for 120 min. The incubation of the tumor cells with dextromethorphan or dimemorfan resulted in a decrease in the proportion of the viable cells (less than 25% after 120 min). However, no significant change was observed in the proportion of the viable tumor cells during the incubation with and without the other drugs (80-83% after 120 min). In addition, mice given the tumor cells i.p. were injected intraperitoneally with drugs (20-80 mg/kg/day) once daily for 5 successive days, and their survival time was observed. There was a slight difference in the survival time between mice treated with and without dextromethorphan or dimemorfan. However, a significant difference was found in the survival time between mice treated with and without dextromethorphan when mice given Ehrlich carcinoma cells were injected with the drug (40 mg/kg/time) twice a day for 5 days (about 18 days and 29 days). These results indicate that dextromethorphan and dimemorfan are cytotoxic to the tumor cells in vitro and in vivo.

Topics: Animals; Antineoplastic Agents; Antitussive Agents; Carcinoma, Ehrlich Tumor; Cell Survival; Cells, Cultured; Codeine; Dextromethorphan; Female; Mice; Morphinans; Sarcoma 180; Thebaine