Binding of dimemorfan to sigma-1 receptor and its anticonvulsant and locomotor effects in mice, compared with dextromethorphan and dextrorphan

Dextromethorphan ((+)-3-methoxy-N-methylmorphinan, DM) has been shown to ha ve both anticonvulsant and neuroprotective effects. The mechanisms of these CNS effects of DM have been suggested to be associated with the low-affini ty, noncompetitive, N-methyl-D-aspartate (NMDA) antagonism of DM and/or the high-affinity DM/sigma receptors. DM is largely O-demethylated into the ph encyclidine (PCP)-like compound dextrorphan (DR), which may limit its thera peutic use by producing PCP-like adverse effects, such as hyperrocomotion. 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 n ot to form DR. This study therefore characterized the binding of DF to the sigma receptors and NMDA-linked PCP sites and examined the anticonvulsant a s well as locomotor effects of DF:in mice in comparison with those of DM an d DR. We found that DF, DM, and DR were relative high-affinity ligands at s igma-1 receptors (K-i = 151, 205, 144 nM, respectively) while all of them w ere with low affinity at sigma-2 receptors (K-i = 4-11 mu M). only DR exhib ited moderate affinity for PCP sites (K-i = 0.9 mu M), whereas DF(K-i = 17 mu M) and DM (K-i = 7 mu M) were much less active. DF, DM and DR produced p rominent anticonvulsant effects in mice as measured by the supramaximal ele ctroshock test with comparable potency (ED50 similar to 70 mu mol/kg, i.p.) . At the tested doses (20-260 mu mol/kg, i.p.), DM and DR exhibited biphasi c effects on the locomotor activity whereas DF produced a consistent dose-d ependent decrease. These results revealed that, unlike DM and DR, DF did no t cause a PCP-like hyperlocomotion adverse effect that is parallel with the PCP sites binding data. Furthermore, since they have equipotent anticonvul sant 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 ma y not be the requisite for mediating the anticonvulsant activity of these D M 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 ant itussive effect. (C) 1999 Elsevier Science B.V. All rights reserved.