Design and pharmacological activity of glycinamide and N-methoxy amide derivatives of analogs and constitutional isomers of valproic acid

摘要: Abstract A series of glycinamide conjugates and N-methoxy amide derivatives valproic acid (VPA) analogs constitutional isomers were synthesized evaluated for anticonvulsant activity. Of all compounds tested, only N-methoxy-valnoctamide (N-methoxy-VCD) possessed better activity than VPA in the following tests: maximal electroshock, subcutaneous metrazol, 6-Hz (32-mA) seizure tests. In mice, ED50 values N-methoxy-VCD 142 mg/kg (maximal electroshock test), 70 mg/kg (subcutaneous metrazol 35 mg/kg (6-Hz its neurotoxicity TD50 was 118 mg/kg. rats, test 36 mg/kg protective index (PI = TD50/ED50) > 5.5. rat pilocarpine-induced status epilepticus model, demonstrated full protection at 200 mg/kg, without any neurotoxicity. N-Methoxy-VCD tested ability to induce teratogenicity a mouse strain susceptible VPA-induced found be nonteratogenic, although it caused some resorptions. Nevertheless, safety margin still maintained between doses that On basis these results, is good candidate further evaluation as new central nervous system drug.