Oxazepam esters. 3. Intrinsic activity, selectivity, and prodrug effect

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Abstract
Oxazepam (7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-3H-1,4-benzodiazepin-2-one) is a widely used centrally acting drug. Antimetrazol and muscle relaxant activities of 11 aliphatic esters of oxazepam were studied as a function of time in mice. The esters given i.v. retained antimetrazol activity, while muscle relaxant activity was generally decreased. The administration of a dose equivalent to the antimetrazol ED50 caused constant oxazepam brain levels for most esters; but the intrinsic anticonvulsant activity of the intact ester is insignificant. The dimethylphenylpropionyl ester appeared to antagonize the effect of oxazepam, as it elevated the free oxazepam level required to achieve the ED50 in the antimetrazol assay. The administration of doses equivalent to the muscle relaxant ED50 values caused no correlation with total brain benzodiazepine levels, suggesting that changes in the selectivity of action are due to different sites of action.