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

• Published in: Epilepsy & behavior Vol. 22; no. 3; pp. 461 - 468
• Main Authors: Pessah, Neta, Yagen, Boris, Hen, Naama, Shimshoni, Jakob A., Wlodarczyk, Bogdan, Finnell, Richard H., Bialer, Meir
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2011
• Subjects: 6-Hz psychomotor seizure test; Amides - chemistry; Amides - therapeutic use; Animals; Anticonvulsants - chemistry; Anticonvulsants - therapeutic use; Convulsants - toxicity; Disease Models, Animal; Electroshock - adverse effects; Female; Glycinamide conjugates; Isomerism; Male; Maximal electroshock seizure test Subcutaneous metrazol seizure test; Mice; N-methoxy derivatives; Neural Tube Defects - chemically induced; Neurology; 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; Valproic acid isomers and analogues; Glycinamide conjugates; N-methoxy derivatives; Valproic acid isomers and analogues; 6-Hz psychomotor seizure test; Maximal electroshock seizure test Subcutaneous metrazol seizure test
• ISSN: 1525-5050; 1525-5069; 1525-5069
• DOI: 10.1016/j.yebeh.2011.08.026

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 ED50 values of N-methoxy-VCD were 142mg/kg (maximal electroshock test), 70mg/kg (subcutaneous metrazol test), and 35mg/kg (6-Hz test), and its neurotoxicity TD50 was 118mg/kg. In rats, the ED50 of N-methoxy-VCD in the subcutaneous metrazol test was 36mg/kg and its protective index (PI=TD50/ED50) 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 ED50 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. ► N-Methoxy-valnoctamide has better anticonvulsant activity than valproic acid. ► The ED50 values of N-methoxy-valnoctamide in mice were 142mg/kg in the maximal electroshock test, 70mg/kg in the subcutaneous metrazol test, and 35mg/kg in the 6-Hz test. ► The ED50 of N-methoxy-valnoctamide in rats in the subcutaneous metrazol test was 36mg/kg and its protective index (TD50/ED50) was >5.5.