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

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.