| Summary: | 博士 === 國立陽明大學 === 藥理學研究所 === 87 === Dimemorfan (DF, (+)-3-methyl-N-methylmorphinan) is an analog of dextromethorphan (DM, (+)-3-methoxy-N-methylmorphinan). Although DF has been used as an antitussive for more than 20 years, other CNS pharmacological effects are not reported. The aims of the present studies were to examine the pharmacokinetics, the anticonvulsant as well as neurological impairment effects, the binding to the sigma and NMDA-linked PCP receptors, and effects on transmitter amino acid release from rat hippocampal slices of DF, in comparison with those of DM and dextrorphan (DR, an active metabolite of DM). The results obtained were summarized as the following: The pharmacokinetics of DF in rats was studied after 4~12 mg/kg intravenous (iv) bolus injection. Plasma concentration-time profiles of DF were fitted by a two-compartment open model. The dose-related results indicated the pharmacokinetics of DF in rat was linear and DF could not lead to retardation of a drug''s elimination. DF easily entered and almost distributed evenly into the brain regions and mean concentration of DF was approximately ten-fold of that in plasma 120 min after DF iv injection. The much higher brain concentration of DF may be due to its effects on regional circulation, as DF is thought to exhibit central effects. DF, DM and DR produced prominent anticonvulsant effects in mice as measured by the maximal electroshock test (MES) with comparable potency. DF was similar to DM that could protect mice from death and prolong the latency time to death induced by NMDA. At the tested doses (20~260 mm/kg, i.p.), DM and DR exhibited biphasic effects whereas DF produced a consistent dose-dependent decrease on the locomotor activity. These results revealed that, unlike DM and DR, DF did not cause PCP-like hyperlocomotion. Although all of the tested compounds produced dose-related neurological impairment in rotorod performance, the protective index value (PI = rotorod TD50 / MES ED50) of DF, similar with DM but superior to DR, was compatible with the criterion for anticonvulsant drug evaluation. In receptor binding experiments, DF, DM, and DR showed relative high affinity ligands at sigma-1 receptors while all of them were with low affinity at sigma-2 receptors. Only DR exhibited moderate affinity for PCP sites, whereas DF and DM were much less active. All of these three drugs significantly reduced the high concentration of potassium-evoked glutamate release from rat hippocampal slices. We suggest that the anticonvulsant action of these compounds may be due to their ability to decreased glutamate release. In conclusion, the very low affinity of DF at PCP sites suggests that the anticonvulsant activities of these DM analogs may be essentially acting on the sigma-1 receptors, but not necessarily on the PCP sites. The anticonvulsant action of DF may be due to its ability to decreased glutamate release. Given the history of safety and relative less adverse effects of DF in man, it appears to be an attractive compound that is worthy further studying on its CNS effects other than the antitussive effects.
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