title: P-retigabine: an N-propargyled retigabine with improved brain distribution and enhanced antiepileptic activity.
abstract: Retigabine (RTG, [ethyl N-[2-amino-4-[(4-fluorophenyl)methyl]amino] phenyl] carbamate]) is a first-in-class antiepileptic drug that acts by potentiating neuronal KCNQ potassium channels; however, it has less than optimal brain distribution. In this study, we report that P-RTG (ethyl N-[2-amino-4-((4-fluorobenzyl)(prop-2-ynyl)amino)phenyl]carbamate), an RTG derivative that incorporates a propargyl group at the N position of the RTG linker, exhibits an inverted brain distribution compared with RTG. The brain-to-plasma concentration ratio of P-RTG increased to 2.30 compared with 0.16 for RTG. However, the structural modification did not change the drug's potentiation potency, subtype selectivity, or RTG molecular determinants on KCNQ channels. In addition, in cultured hippocampal neurons, P-RTG exhibited a similar capability as RTG for suppressing both induced and spontaneous action potential firing. Notably, P-RTG antiepileptic activity in the maximal electroshock (MES)-induced mouse seizure model was significantly enhanced to a value 2.5 times greater than that of RTG. Additionally, the neurotoxicity of P-RTG in the rotarod test was comparable with that of RTG. Collectively, our results indicate that the incorporation of a propargyl group significantly improves the RTG brain distribution, supporting P-RTG as a promising antiepileptic drug candidate. The strategy for improving brain-to-plasma distribution of RTG might be applicable for the drug development of other central nervous system diseases.
authors.affiliation: State Key Laboratory of Drug Research (P.Z., H.X., X.C., X.P., L.W., L.Z., Z.G.), and National Center for Drug Screening (Y.Z., F.C., X.L., F.N.), State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, and Graduate School, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Pingzheng
authors.initials: P
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Drug Research (P.Z., H.X., X.C., X.P., L.W., L.Z., Z.G.), and National Center for Drug Screening (Y.Z., F.C., X.L., F.N.), State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, and Graduate School, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Yangming
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Drug Research (P.Z., H.X., X.C., X.P., L.W., L.Z., Z.G.), and National Center for Drug Screening (Y.Z., F.C., X.L., F.N.), State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, and Graduate School, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Drug Research (P.Z., H.X., X.C., X.P., L.W., L.Z., Z.G.), and National Center for Drug Screening (Y.Z., F.C., X.L., F.N.), State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, and Graduate School, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Drug Research (P.Z., H.X., X.C., X.P., L.W., L.Z., Z.G.), and National Center for Drug Screening (Y.Z., F.C., X.L., F.N.), State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, and Graduate School, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Xueqin
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Drug Research (P.Z., H.X., X.C., X.P., L.W., L.Z., Z.G.), and National Center for Drug Screening (Y.Z., F.C., X.L., F.N.), State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, and Graduate School, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Drug Research (P.Z., H.X., X.C., X.P., L.W., L.Z., Z.G.), and National Center for Drug Screening (Y.Z., F.C., X.L., F.N.), State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, and Graduate School, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Pi
authors.affiliation: State Key Laboratory of Drug Research (P.Z., H.X., X.C., X.P., L.W., L.Z., Z.G.), and National Center for Drug Screening (Y.Z., F.C., X.L., F.N.), State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, and Graduate School, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Lipeng
authors.initials: L
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Drug Research (P.Z., H.X., X.C., X.P., L.W., L.Z., Z.G.), and National Center for Drug Screening (Y.Z., F.C., X.L., F.N.), State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, and Graduate School, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhan
authors.affiliation: State Key Laboratory of Drug Research (P.Z., H.X., X.C., X.P., L.W., L.Z., Z.G.), and National Center for Drug Screening (Y.Z., F.C., X.L., F.N.), State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, and Graduate School, Chinese Academy of Sciences, Shanghai, People's Republic of China zbgao@simm.ac.cn fjnan@simm.ac.cn.
authors.forename: Fajun
authors.initials: F
authors.lastname: Nan
authors.affiliation: State Key Laboratory of Drug Research (P.Z., H.X., X.C., X.P., L.W., L.Z., Z.G.), and National Center for Drug Screening (Y.Z., F.C., X.L., F.N.), State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, and Graduate School, Chinese Academy of Sciences, Shanghai, People's Republic of China zbgao@simm.ac.cn fjnan@simm.ac.cn.
authors.forename: Zhaobing
authors.initials: Z
authors.lastname: Gao
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016466:CHO Cells; D002219:Carbamates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D051656:KCNQ Potassium Channels / Q000378:metabolism*; D008297:Male; D051379:Mice; D010655:Phenylenediamines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: D000927:Anticonvulsants; D002219:Carbamates; D051656:KCNQ Potassium Channels; D010655:Phenylenediamines; C000595570:ethyl N-(2-amino-4-((4-fluorobenzyl)(prop-2-ynyl)amino)phenyl)carbamate; C101866:ezogabine