Novel Anticonvulsant Analogs of Dextromethorphan: Improved Efficacy, Potency, Duration and Side-Effect Profile
WALTER REED ARMY INST OF RESEARCH WASHINGTON DC
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The anticonvulsant and neuroprotective activity of dextromethorphan DM, -3-methyl-17-methylmorphinan may be, in part, due to its metabolism to the PCP-like compound dextrorphan DX. We evaluated the anticonvulsant activity and neurological impairing effects in rats of three novel analogs of DM which, based upon their 3position substituents, would either not be expected to be metabolized to DX, or might do so at a reduced rate. The DM analogs were determined to be more potent and more efficacious than DM against maximal electroshock MES convulsions two of the analogs, namely AHN1-036 -3- ethoxy-17-methylmorphinan AND AHN1-037 -3-2-propoxy-17-methylmorphinan, were equipotent to DX. AHN1-036 and AHN1-037 exhibited a duration of action 1-2 hrs slightly longer than DX 0. 5-1 hr and similar to DM 2-4 hr. The anticonvulsant effect of AHN649 persisted 4-6 hrs. Against flurothyl convulsions DM was proconvulsant, DX was anticonvulsant, and the DM analogs were inactive. In contrast, N-methyl-D-Aspartate NMDA convulsions were antagonized by pretreatment with DM and the DM analogs, albeit with a potency approximately 10 times less than that of DX.