Chapter 13 Enantioselective recognition of two anticonvulsants, FCE 26743 and FCE 28073, by MAO, and relationship between MAO-B inhibition and FCE 26743 concentrations in rat brain

The two alanine derivatives—namely, FCE 26743 [(S)-244- (3-fluorobenzyloxy)-benzylamino)propionamide] and its enantiomeric counterpart FCE 28073, have been found to display similar, potent anticonvulsant activities in the animal models of epilepsy. This chapter reports on the in vitro and ex vivo monoamine oxidase (MAO) inhibitory properties of FCE 26743 and FCE 28073 in the rat and on the in vitro MAO inhibitory properties of aldehyde [4-(3-fluorobenzyloxy)benzaldehyde], which would be produced by MAO if FCE 26743 and/or FCE 28073 are the substrates of that enzyme. In addition, to examine whether products formed by MAO-independent oxidative metabolism of FCE 26743 could contribute to its MAO-B inhibitory properties, experiments have been carried out in rats pretreated with SKF-525A, an inhibitor of oxidative drug metabolism. The relationship between ex vivo MAO-B inhibition and FCE 26743 concentrations in the rat brain was investigated in the chapter by developing a pharmacokinetic-pharmacodynamic model. In the in vitro studies where the rat brain homogenates, FCE 26743 was found to be a potent inhibitor of MAO-B and a weak inhibitor of MAO-A, while FCE 28073 was approximately 10-times less potent.