Identification and Electrophysiological Evaluation of 2-Methylbenzamide Derivatives as Nav1.1 Modulators

Voltage-gated sodium channels (Na_v) are crucial to the initiation and propagation of action potentials (APs) in electrically excitable cells, and during the past decades they have received considerable attention due to their therapeutic potential. Here, we report for the first time the synthesis and the electrophysiological evaluation of 16 ligands based on a 2-methylbenzamide scaffold that have been identified as Na_v1.1 modulators. Among these compounds, N,N′-(1,3-phenylene)bis(2-methylbenzamide) (3a) has been selected and evaluated in ex-vivo experiments in order to estimate the activation impact of such a compound profile. It appears that 3a increases the Na_v1.1 channel activity although its overall impact remains moderate. Altogether, our preliminary results provide new insights into the development of small molecule activators targeting specifically Na_v1.1 channels to design potential drugs for treating CNS diseases.