N-(benzyloxycarbonyl)glycine esters and amides as new anticonvulsants.
Glycine is a small neutral amino acid exhibiting weak anticonvulsant activities in vivo. Recently, studies have demonstrated that N-(benzyloxycarbonyl)glycine (1) antagonized seizures superior to glycine in addition to activity in the maximal electroshock (MES) test, a convulsive model where glycine is inactive. In the present study a series of ester and amide derivatives of 1 as well as esters of N-(3-phenylpropanoyl)glycine (5) have been prepared. The compounds were evaluated in the MES test as well as in several chemically induced seizure models. Among the derivatives investigated, N-(benzyloxycarbonyl)glycine benzylamide (16) was the most potent compound exhibiting an anticonvulsant activity in the MES test comparable to the drug phenytoin. Median effective doses (ED50) of 4.8 and 11.6 mg/kg were determined at 30 min and 3 h after i.p. administration, respectively. Compound 16 also effectively suppressed tonic seizures in different chemically induced models such as the strychnine, 3-mercaptopropionic acid, and pentylenetetrazole tests. Moreover, the compound studied here did not show acute neurotoxicity in the rotorod test up to a dose of 150 mg/kg. It is concluded that N-(benzyloxycarbonyl)glycine amides, especially 16, are potent anticonvulsant agents.
Geurts
M
M
Department of Pharmaceutical Sciences, School of Pharmacy, Faculty of Medicine, Catholic University of Louvain, Brussels, Belgium.
Poupaert
J H
JH
Scriba
G K
GK
Lambert
D M
DM
D015097:3-Mercaptopropionic Acid; D000577:Amides; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D004952:Esters; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009498:Neurotoxins / Q000494:pharmacology; D010433:Pentylenetetrazole; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018009:Receptors, Glycine / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control*; D013116:Spinal Cord / Q000378:metabolism; D013331:Strychnine / Q000494:pharmacology
D000577:Amides; D000927:Anticonvulsants; D004952:Esters; D009498:Neurotoxins; D018009:Receptors, Glycine; D015097:3-Mercaptopropionic Acid; D013331:Strychnine; D005998:Glycine; D010433:Pentylenetetrazole