TY - JOUR T1 - P-Retigabine: An <em>N</em>-Propargyled Retigabine with Improved Brain Distribution and Enhanced Antiepileptic Activity JF - Molecular Pharmacology JO - Mol Pharmacol SP - 31 LP - 38 DO - 10.1124/mol.114.095190 VL - 87 IS - 1 AU - Pingzheng Zhou AU - Yangming Zhang AU - Haiyan Xu AU - Fei Chen AU - Xueqin Chen AU - Xiaoying Li AU - Xiaoping Pi AU - Lipeng Wang AU - Li Zhan AU - Fajun Nan AU - Zhaobing Gao Y1 - 2015/01/01 UR - http://molpharm.aspetjournals.org/content/87/1/31.abstract N2 - 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. ER -