α-fluoro-2,2,3,3-tetramethylcyclopropanecarboxamide, a novel potent anticonvulsant derivative of a cyclic analogue of valproic acid

2,2,3,3-Tetramethylcyclopropanecarboxylic acid (TMCA, 4) is a cyclic analogue of the antiepileptic drug (AED) valproic acid (VPA) (1). α-F, α-Cl, R-Br, and R-methyl derivatives of 4 and their amides were synthesized and tested in rodent models for anticonvulsant potency and AED-induced teratogenicity. In the anticonvulsant rat-maximal electroshock (MES) and subcutaneous metrazol (scMet) tests, α-Cl-TMCD (17) had ED ₅₀ values of 97 and 27 mg/kg, respectively. α-F-TMCD (11) was 120 times more potent than VPA in the rat-scMet test (ED ₅₀) 6 mg/kg) and had a protective index (PI) TD ₅₀/ED ₅₀) of 20. In the 6 Hz psychomotor mouse model 11 had ED ₅₀ values of 57 mg/kg (32 mA) and 59 mg/kg (44 mA). The ED50 values of 11 in the hippocampal-kindled rat model and in the pilocarpine-induced-status rat model were 30 and 23 mg/kg, respectively. Unlike 1, 11 was nonteratogenic in mice. This novel compound has the potential to become a candidate for development as a new potent and safe antiepileptic and CNS drug.