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

Epilepsy Behav. 2011 Nov;22(3):461-8. doi: 10.1016/j.yebeh.2011.08.026. Epub 2011 Sep 29.


A series of glycinamide conjugates and N-methoxy amide derivatives of valproic acid (VPA) analogs and constitutional isomers were synthesized and evaluated for anticonvulsant activity. Of all compounds synthesized and tested, only N-methoxy-valnoctamide (N-methoxy-VCD) possessed better activity than VPA in the following anticonvulsant tests: maximal electroshock, subcutaneous metrazol, and 6-Hz (32-mA) seizure tests. In mice, the ED(50) values of N-methoxy-VCD were 142 mg/kg (maximal electroshock test), 70 mg/kg (subcutaneous metrazol test), and 35 mg/kg (6-Hz test), and its neurotoxicity TD(50) was 118 mg/kg. In rats, the ED(50) of N-methoxy-VCD in the subcutaneous metrazol test was 36 mg/kg and its protective index (PI=TD(50)/ED(50)) was >5.5. In the rat pilocarpine-induced status epilepticus model, N-methoxy-VCD demonstrated full protection at 200mg/kg, without any neurotoxicity. N-Methoxy-VCD was tested for its ability to induce teratogenicity in a mouse strain susceptible to VPA-induced teratogenicity and was found to be nonteratogenic, although it caused some resorptions. Nevertheless, a safety margin was still maintained between the ED(50) values of N-methoxy-VCD in the mouse subcutaneous metrazol test and the doses that caused the resorptions. On the basis of these results, N-methoxy-VCD is a good candidate for further evaluation as a new anticonvulsant and central nervous system drug.

MeSH terms

  • Amides* / chemistry
  • Amides* / therapeutic use
  • Animals
  • Anticonvulsants / chemistry*
  • Anticonvulsants / therapeutic use*
  • Convulsants / toxicity
  • Disease Models, Animal
  • Electroshock / adverse effects
  • Female
  • Isomerism
  • Male
  • Mice
  • Neural Tube Defects / chemically induced
  • Pentylenetetrazole / toxicity
  • Rats
  • Rats, Sprague-Dawley
  • Seizures / drug therapy*
  • Seizures / etiology
  • Structure-Activity Relationship
  • Valproic Acid* / analogs & derivatives
  • Valproic Acid* / chemistry
  • Valproic Acid* / therapeutic use


  • Amides
  • Anticonvulsants
  • Convulsants
  • Valproic Acid
  • Pentylenetetrazole