Of the few cannabinoids that are available and that have been tested thus far, cannabidiol (CBD) has shown the most promising potential as a nonpsychoactive antiepileptic drug. However, there is a paucity of data on the anticonvulsant potential of CBD analogs and on the general structure-(anticonvulsant) activity requirements for these novel types of potential therapeutic drugs. The present interdisciplinary research is aimed at evaluating the anticonvulsant potential and structure-activity relationships of new CBD analogs in laboratory animals. The major objectives are to synthesize new CBD derivatives and related cannabinoid analogs and, to evaluate their effects for anticonvulsant activity and neurotoxicity in rats and behavioral activity in rabbits. To determine 3-dimensional spacial and other structural-activity requirements, the following types of CBD analogs will be synthesized: Analogs with varying degrees of monoterpene saturation and CBD conformational isomers; analogs with modifications, of the aromatic nucleus especially with substituents at the 4' positions; the 1"""""""",1"""""""" dimethylheptyl analog of CBD; and for those analogs showing good anticonvulsant activity, water solubilized derivatives. Compounds will be evaluated for anticonvulsant activity using audiogenic seizure (AS) rats. Neurotoxicity of analogs will be ascertained in the standard rat rolling-roller test. Moreover, the potential for psychoactivity will be determined by assessing drug effects on convulsant behavior in the cannabinoid seizure-susceptible rabbit model.
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