Multifunctional Hybrid Compounds Derived from 2-(2,5-Dioxopyrrolidin-1-yl)-3-methoxypropanamides with Anticonvulsant and Antinociceptive Properties.

Abstract

The focused set of new pyrrolidine-2,5-diones as potential broad-spectrum hybrid anticonvulsants was described. These derivatives integrate on the common structural scaffold the chemical fragments of well-known antiepileptic drugs such as ethosuximide, levetiracetam, and lacosamide. Such hybrids demonstrated effectiveness in two of the most widely used animal seizure models, namely, the maximal electroshock (MES) test and the psychomotor 6 Hz (32 mA) seizure models. Compound 33 showed the highest anticonvulsant activity in these models (ED50 MES = 79.5 mg/kg, ED50 6 Hz = 22.4 mg/kg). Compound 33 was also found to be effective in pentylenetetrazole-induced seizure model (ED50 PTZ = 123.2 mg/kg). In addition, 33 demonstrated effectiveness by decreasing pain responses in formalin-induced tonic pain, in capsaicin-induced neurogenic pain, and notably in oxaliplatin-induced neuropathic pain in mice. The pharmacological data of stereoisomers of compound 33 revealed greater anticonvulsant activity by R(+)-33 enantiomer in both MES and 6 Hz seizure models.