New morphinan derivatives with negligible psychotropic effects attenuate convulsions induced by maximal electroshock in mice.
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 x 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 sigma(1) receptors, while they all had low affinity at sigma(2) 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 sigma(1) receptors.
Kim
Hyoung-Chun
HC
Neurotoxicology Program, College of Pharmacy, Korea Institute of Drug Abuse, Kangwon National University, Chunchon 200-701, South Korea. kimhc@cc.kangwon.ac.kr
Shin
Chan Young
CY
Seo
Dong Ook
DO
Jhoo
Jin Hyeong
JH
Jhoo
Wang-Kee
WK
Kim
Won-Ki
WK
Shin
Eun-Joo
EJ
Lee
Young-Ho
YH
Lee
Phil Ho
PH
Ko
Kwang Ho
KH
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D003915:Dextromethorphan / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009019:Morphinans / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D011869:Radioligand Assay; D017480:Receptors, sigma / Q000378:metabolism; D012640:Seizures / Q000209:etiology / Q000517:prevention & control*
D000927:Anticonvulsants; D009019:Morphinans; D017480:Receptors, sigma; C028657:3-methoxymorphinan; D003915:Dextromethorphan; C054116:norlevorphanol