New morphinan derivatives with negligible psychotropic effects attenuate convulsions induced by maximal electroshock in mice

Neuropsychotoxic and Neuroprotective Potentials of Dextromethorphan and Its Analogs

“…DM has been reported to suppress seizures induced by maximal electroshock (34,35), NMDA (36,37), amygdala kindling (38,39), kainic acid (40,41), BAY k-8644 (42,43), and trimethyltin (44). DX (the dextrorotatory form of levorphanol) has similarly been reported to suppress seizures induced by maximal electroshock (34), NMDA (36), and BAY k-8644 (42,43).…”

“…Indeed, it has been suggested that the primary mechanism of action of DM is simply a blockade of certain ion channels (9). In addition to its direct effects on voltage-gated cation channels, DM might also have anticonvulsant effects resulting from its binding to σ receptors (9,34,44,47,55), although the role of σ receptors in anticonvulsant drug actions remains to be determined. Both anticonvulsant and proconvulsant effects have been reported for σ-site ligands (9).…”

Neuropsychotoxicity of Abused Drugs: Potential of Dextromethorphan and Novel Neuroprotective Analogs of Dextromethorphan With Improved Safety Profiles in Terms of Abuse and Neuroprotective Effects

“…2) that are safe behaviorally (29, 32 -34) and modified in positions 3 and 17 of the morphinan ring on maximal electroshock convulsions (MES) in mice (32). We found that DM, the major DM metabolite dextrorphan (DX), 3-allyloxy-17-methylmorphinan (AM), and 3-cyclopropylmethoxy-17-methylmorphinan (CM) had anticonvulsant effects against MES, while other DM metabolites, such as 3-methoxymorphinan (MM) and 3-hydroxymorphinan (3-HM), showed no anticonvulsant effects (32). We also observed that DM, DX, AM, and CM have high affinity to sigma 1 receptors, while they all have low affinity to sigma 2 receptors.…”

“…In contrast, AM and CM have very low affinities for PCP sites, suggesting that PCP sites are not required for their anticonvulsant actions (31,32). Our results suggest that our DM analogs are promising anticonvulsants that lack behavioral side effects, and their anticonvulsant actions may be, at least in part, mediated via sigma 1 receptors (32,33). We have also demonstrated that another DM analog, dimemorfan (DF), has a promising anticonvulsant effect with negligible behavioral side effects (33) (see Table 1 and Figs.…”

Concise Synthesis of Dimemorfan (DF) Starting from 3-Hydroxymorphinan (3-HM)

“…1). [2][3][4][5][6][7][8][9][10][11][12][13][14] However, DM is reported toxic in children and abuse potential in adolescent youths. Therefore, a dextromethorphan analog that retains its anticonvulsant and neuroprotective activities without being converted into dextrorphan in vivo would be ideal.…”