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

Abstract

Interest in dextromethorphan (DM) has been renewed because of its anticonvulsant and neuroprotective properties. However, DM at supra-antitussive doses can produce psychotomimetic effects in humans. Recently, we demonstrated that DM exerts psychotropic effects in mice [Neurosci. Lett. 288 (2000) 76, Life Sci. 69 (2001) 615]. We synthesized a series of compounds with a modified morphinan ring system, with the intention of developing compounds that retain the anticonvulsant activity with weak psychotropic effects [Bioorg. Med. Chem. Lett. 11 (2001) 1651]. In order to extend our understanding of the pharmacological intervention of these morphinans, we assessed their behavioral effects, and then examined whether they exert protective effects on maximal electroshock convulsions (MES) in mice. Repeated treatment (20 or 40 mg/kg, i.p./day × 7) with DM or dextrorphan (a major metabolite of DM; DX) significantly enhanced locomotor activity in a dose-related manner. This locomotor stimulation was accentuated more in the animals treated with DX, and might be comparable to that of phencyclidine (PCP). By contrast, treatment with a metabolite of DM [3-methoxymorphinan (3MM) or 3-hydroxymorphinan (3HM)], 3-allyloxy-17-methylmorphinan (CPK-5), or 3-cyclopropylmethoxy-17-methylmorphinan (CPK-6) did not significantly alter locomotor activity or patterns. The behavioral effects mediated by these morphinans and PCP paralleled the effects of conditioned place preference. DM, DX, CPK-5, and CPK-6 had anticonvulsant effects against MES, while 3MM and 3HM did not show any anticonvulsant effects. We found that DM, DX, CPK-5 and CPK-6 were high-affinity ligands at σ1 receptors, while they all had low affinity at σ2 receptors. DX had relatively higher affinity for the PCP sites than DM. By contrast, CPK-5 and CPK-6 had very low affinities for PCP sites, suggesting that PCP sites are not requisites for their anticonvulsant actions. Our results suggest that the new morphinan analogs are promising anticonvulsants that are devoid of PCP-like behavioral side effects, and their anticonvulsant actions may be, in part, mediated via σ1 receptors. © 2003 Elsevier Science Inc. All rights reserved.