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Ureylene anticonvulsants and related compounds
J R Dimmock1, S C Vashishtha, J P Stables
1College of Pharmacy and Nutrition, University of Saskatchewan, Canada.
Die Pharmazie
|August 17, 2000
Summary
Researchers explored novel anticonvulsant compounds, focusing on ureylenes to improve upon semicarbazones. Several compounds demonstrated significant protection against seizures in mice, with some showing promise for oral administration without neurotoxicity.
Area of Science:
- Medicinal Chemistry
- Neuropharmacology
- Drug Discovery
Background:
- Previous studies identified aryl semicarbazones with anticonvulsant activity, suggesting interaction with hydrophobic (Area A) and hydrogen bonding (Area B) sites.
- The carbimino group in semicarbazones presents potential toxicity and acid lability issues.
- Related ureylene compounds were investigated to overcome semicarbazone limitations.
Purpose of the Study:
- To design and synthesize novel ureylene derivatives with potential anticonvulsant activity.
- To explore the structure-activity relationships of these compounds, particularly concerning interactions with proposed binding site areas A, B, and C.
- To identify promising lead compounds for further development as anticonvulsant agents.
Main Methods:
- Synthesis of a series of ureylene compounds designed to interact with specific binding site areas.
- Evaluation of anticonvulsant activity using the maximal electroshock (MES) seizure screen in mice.
- Assessment of neurotoxicity and oral activity in rats.
Main Results:
- Most synthesized ureylene compounds showed protection against MES-induced seizures in mice.
- Compounds 1d and 1j, featuring an alpha-methylbenzyl group, exhibited significant anticonvulsant effects.
- Binding site areas A and C could accommodate lipophilic groups of varying sizes.
- Several compounds, including 1d, 1f, 1j, and 2d, were orally active in rats and lacked neurotoxicity at effective doses.
Conclusions:
- Ureylene derivatives represent a promising class of compounds for anticonvulsant drug development.
- Specific structural modifications, such as the incorporation of an alpha-methylbenzyl group, enhance anticonvulsant potency.
- Compounds 1d, 1f, 1j, and 2d serve as valuable prototypic molecules for future research into novel anticonvulsants.