P-Retigabine: An N-Propargyled Retigabine with Improved Brain Distribution and Enhanced Antiepileptic Activity

Abstract

Retigabine (RTG,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.

Identification and Evaluation of Antiepileptic Activity of C21 Steroidal Glycosides from the Roots of Cynanchum wilfordii

“…Under identical conditions, the ED 50 value of retigabine, a first-line antiepilepsy drug, was 15.0 mg/kg. 34 The MES test results suggested that these C 21 steroidal glycosides deserve further evaluation as potential candidates for the development of therapeutic agents against epilepsy. Detailed MES experimental data of these compounds are available in Table S1 (Supporting Information).…”

“…Mouse MES-Induced Seizure Assays. 34 KM male mice weighing 20 ± 2 g were purchased from the Shanghai Slac Laboratory Animal Co., Ltd. (Shanghai, People's Republic of China). At the conclusion of each experiment, animals were euthanized in accordance with the guidelines established by the National Institutes of Health Guide for the Care and Use of Laboratory Animals, strictly following protocols that were approved by the institutional animal care and use committees.…”

Functional and behavioral signatures of Kv7 activator drug subtypes

“…Since the recognition of the powerful effects of retigabine (and its close analog flupirtine) on Kv7 channels, efforts have focused on identification of Kv7 activators with distinct subtype specificity, enhanced potency, or other pharmacological properties that may enhance their utility 4,9,17,36–39 . A heterogeneous set of compounds with Kv7 activator effects has been described (comprehensively reviewed recently by Miceli et al 4 ), along with a growing understanding of their mechanisms of action.…”

Treatment of myotonia congenita with retigabine in mice

“…As the same mice were used for all behavioral experiments, at least 2 days were given between studies to allow time for drug elimination. The plasma half-life for retigabine in mice is 7 hours (Zhou, et al, 2015) so 2 days represents more than 6 half-lives.…”