Anticonvulsant effects N-(2-propylpentanoyl) urea

Abstract

Anticonvulsant activity, lethality and neurotoxicity of a new valproic acid analogue, n-(2-propylpentanoyl) urea (VPU), and valproic acid (VPA), as a reference drug, were investigated in mice and rats. Microdialysis technique was used to investigate the effect of VPU on rat cortical amino acid neurotransmitters. Intraperitoneally administered VPA and VPU demonstrated the same spectrum of anticonvulsant activity, being active in maximal electroshock (MES) test, pentylenetetrazole (PTZ) test and bicuculline test but ineffective in strychnine test. In comparison to VPA, VPU was relatively equipotent in bicuculline test but exerted higher potency in MES and PTZ tests. The median effective dose (ED₅₀ ) of VPU in protection against a gamma aminobutylic acidA (GABAA) antagonist, bicuculline, was relatively high (>300 milligram/kilogram body weight (mg/kg B.W.)) Therefore the involvement of GABAA receptor seem to be trivial. The ED₅₀ of VPU was 66 and 57 mg/kg B.W. in MES and PTZ tests respectively while they are 242 and 95 mg/kg B.W. for VPA. These results indicate that VPU exhibits a greater potency in protection against MES and PTZ test than VPA. Based on the relatively high LD₅₀ , 1553 and 838 mg/kg B.W. for VPU. and VPA respectively, and rather low side effects as predicted from its effects on locomotor activity and potentiation of barbiturate sleeping time, VPU appears to offer a greater safety margin as well as a lower unwanted effects than VPA. In brain microdialysis studies, VPA significantly and selectively decreased cortical aspartate while VPU significantly decreased the levels of cortical excitatory (aspartate and glutamate) and inhibitory (glycine and GABA) amino acid neurotransmitters in dose dependent manner. The depression was greatest on glutamate and least on glycine. These may explain the anticonvulsant activity observed. A strong synergistic effect of VPU with the anesthetic used, pentobarbital, is questionable and may account to the non selective depressant effect of VPU. The present studies demonstrated a promissing prospect for VPU to become a candidate for a potent broad spectrum antiepileptic drug with higher margin of safety and lower side effects. However extensive studies are needed to elucidate its precise mechanism of action as well as pharmacological and toxicological profiles.