PRELIMINARY EVALUATION OF THE ANTICONVULSANT ACTIVITY OF A VALPROIC ACID ANALOG - N-(2-PROPYLPENTANOYL) UREA

Anticonvulsant activity, lethality and neurotoxicity of a valproic aci d (VPA) analog, N-(2-propylpentanoyl) urea (VPU) in comparison to its parent compound were investigated in mice. Intraperitoneally administe red VPU demonstrated a higher protection than VPA in both the maximal electroshock seizure (MES) and the pentylenetetrazole (PTZ) tests exhi biting a median effective dose ED50) of 66 and 57 mg/kg, respectively VPU weakly blocked the effect of bicuculline and was ineffective in st rychnine test. Furthermore, VPU was also active orally demonstrating a n ED50 approximately 6 times higher than its ED50 by the intraperitone al route. Based on the relatively high median lethal dose (LD50), 1553 mg/kg, VPU possesses a greater margin of safety (LD50/ED50) than did VPA. Unwanted (side) effects in terms of impairment of motor activity and neurotoxicity were assessed by the rotorod test, locomotor activit y test as well as potentiation of barbiturate sleeping time. The media n neurotoxic dose (TD50 as measured by rotorod test were 625 mg/kg for intraperitoneally given VPU. This finding results in higher protectiv e index (PI = TD50ED50) of VPU (PI = 9.5) than that of VPA (PI = 1.1) implying that, in therapeutic dose, VPU may produce less neurological side effects than did VPA. Superiority of VPU in terms of higher poten cy in parallel with minimal neurological deficit as assessed by rotoro d test was evident throughout the observation period of 12 hours. Simi lar results on locomotor activity as well as potentiation of barbitura te sleeping time were obtained with VPU and VPA. Thus, VPU is preferab ly expected to exert minor degree of CNS depression. Taken altogether, our findings demonstrate greater anticovulsant activity for VPU than for VPA. In addition, this compound is also orally active and seems to offer a greater safety margin in parallel with lower unwanted effects in relation to its parent compound. As indicated by the animal data o btained, VPU is an attractive anticonvulsant candidate for further inv estigation.