title: Design and pharmacological activity of glycinamide and N-methoxy amide derivatives of analogs and constitutional isomers of valproic acid.
abstract: 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.
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Neta
authors.initials: N
authors.lastname: Pessah
authors.forename: Boris
authors.initials: B
authors.lastname: Yagen
authors.forename: Naama
authors.initials: N
authors.lastname: Hen
authors.forename: Jakob A
authors.initials: JA
authors.lastname: Shimshoni
authors.forename: Bogdan
authors.initials: B
authors.lastname: Wlodarczyk
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
authors.forename: Meir
authors.initials: M
authors.lastname: Bialer
mesh_terms: D000577:Amides / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000627:therapeutic use*; D003292:Convulsants / Q000633:toxicity; D004195:Disease Models, Animal; D004597:Electroshock / Q000009:adverse effects; D005260:Female; D007536:Isomerism; D008297:Male; D051379:Mice; D009436:Neural Tube Defects / Q000139:chemically induced; D010433:Pentylenetetrazole / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology; D013329:Structure-Activity Relationship; D014635:Valproic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D000577:Amides; D000927:Anticonvulsants; D003292:Convulsants; D014635:Valproic Acid; D010433:Pentylenetetrazole