title: Effects of dextrorotatory morphinans on brain Na+ channels expressed in Xenopus oocytes.
abstract: We previously demonstrated that dextromethorphan (DM; 3-methoxy-17-methylmorphinan) analogs have neuroprotective effects. Here, we investigated the effects of DM, three of its analogs (DF, 3-methyl-17-methylmorphinan; AM, 3-allyloxy-17-methoxymorphian; and CM, 3-cyclopropyl-17-methoxymorphinan) and one of its metabolites (HM; 3-methoxymorphinan), on Na(+) channel activity. We used the two-microelectrode voltage-clamp technique to test the effects of DM, DF, AM, CM and HM on Na(+) currents (I(Na)) in Xenopus oocytes expressing cRNAs encoding rat brain Nav1.2 alpha and beta1 or beta2 subunits. In oocytes expressing Na(+) channels, DM, DF, AM and CM, but not HM, induced tonic and use-dependent inhibitions of peak I(Na) following low- and high-frequency stimulations. The order of potency for the inhibition of peak I(Na) was AM-CM > DM=DF. The DM, DF, AM and CM-induced tonic inhibitions of peak I(Na) were voltage-dependent, dose-dependent and reversible. The IC(50) values for DM, DF, AM and CM were 116.7+/-14.9, 175.8+/-16.9, 38.6+/-15.5, and 42.5+/-8.5 microM, respectively. DM and its analogs did not affect the steady-state activation and inactivation voltages. AM and CM, but not DM and DF, inhibited the plateau I(Na) more effectively than the peak I(Na) in oocytes expressing inactivation-deficient I1485Q-F1486Q-M1487Q (IFMQ3) mutant channels; the IC(50) values for AM and CM in this system were 8.4+/-1.3 and 8.7+/-1.3 microM, respectively, for the plateau I(Na) and 43.7+/-5.9 and 32.6+/-7.8 microM, respectively, for the peak I(Na). These results collectively indicate that DM and its analogs could be novel Na(+) channel blockers acting on the resting and open states of brain Na(+) channels.
authors.affiliation: Department of Physiology, College of Veterinary Medicine, Institute of Biomedical Science and Technology, Bio/Molecular Informatics Center, Konkuk University, Seoul, Republic of Korea 143-701.
authors.forename: Jun-Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Shin
authors.forename: Sang Min
authors.initials: SM
authors.lastname: Jeong
authors.forename: Byung-Hwan
authors.initials: BH
authors.lastname: Lee
authors.forename: In-Soo
authors.initials: IS
authors.lastname: Yoon
authors.forename: Jun-Hee
authors.initials: JH
authors.lastname: Lee
authors.forename: Sun-Hye
authors.initials: SH
authors.lastname: Choi
authors.forename: Yun Hi
authors.initials: YH
authors.lastname: Kim
authors.forename: Mi Kyung
authors.initials: MK
authors.lastname: Pyo
authors.forename: Sang-Mok
authors.initials: SM
authors.lastname: Lee
authors.forename: Jong Seok
authors.initials: JS
authors.lastname: Chae
authors.forename: Hyewhon
authors.initials: H
authors.lastname: Rhim
authors.forename: Jae-Wook
authors.initials: JW
authors.lastname: Oh
authors.forename: Hyoung-Chun
authors.initials: HC
authors.lastname: Kim
authors.forename: Seung-Yeol
authors.initials: SY
authors.lastname: Nah
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003915:Dextromethorphan / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D015870:Gene Expression; D008564:Membrane Potentials; D008839:Microelectrodes; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects; D021122:Protein Subunits; D018075:RNA, Complementary / Q000378:metabolism; D051381:Rats; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D018696:Neuroprotective Agents; D021122:Protein Subunits; D018075:RNA, Complementary; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D003915:Dextromethorphan