Multitargeted Compounds Derived from (2,5-Dioxopyrrolidin-1-yl)(phenyl)-Acetamides as Candidates for Effective Anticonvulsant and Antinociceptive Agents.

Abstract

We developed a focused set of original hybrid pyrrolidine-2,5-dione derivatives with potent anticonvulsant and antinociceptive properties. These hybrid compounds demonstrated broad-spectrum protective activity in a range of mouse models, such as the maximal electroshock (MES) test, the pentylenetetrazole-induced seizures (PTZ), and the 6 Hz (32 mA) seizures. Compoundshowed the most potent anticonvulsant activity (EDMES = 23.7 mg/kg, ED6 Hz (32 mA) = 22.4 mg/kg, EDPTZ = 59.4 mg/kg). In addition,revealed potent efficacy in the formalin-induced tonic pain. Theseactivities ofare likely mediated by several targets and may result from the inhibition of central sodium/calcium currents and transient receptor potential vanilloid 1 (TRPV1) receptor antagonism. Finally, the lead compoundrevealed drug-like absorption, distribution, metabolism, excretion, toxicity (ADME-Tox) properties in theassays, making it a potential candidate for further development in epilepsy and neuropathic pain indications.