Relevance of benzyloxy group in 2‐indolyl methylamines in the selective MAO‐B inhibition

Previous studies with indolyl derivatives as monoamine oxidase (MAO) inhibitors have shown the relevance of the indole structure for recognition by the active site of this enzyme. We now report a new series of molecules with structural features which determine the selectivity of MAO inhibition. A benzyloxy group attached at position 5 of the indole ring is critical for this selective behaviour. Amongst all of these benzyloxy‐indolyl methylamines, N‐(2‐propynyl)‐2‐(5‐benzyloxyindol)methylamine FA‐73 was the most potent MAO‐B ‘suicide’ inhibitor studied. The K i values for MAO‐A and MAO‐B were 800±60 and 0.75±0.15 n M , respectively. These data represent a selectivity value of 1066 for MAO‐B, being 48 times more selective than L ‐deprenyl (K i values of 376±0.032 and 16.8±0.1 n M for MAO A and MAO‐B, respectively). The IC 50 values for dopamine uptake in striatal synaptosomal fractions from rats were 150±8 μ M for FA‐73 and 68±10 μ M for L ‐deprenyl whereas in human caudate tissue the IC 50 values were 0.36±0.015 μ M for FA‐73 and 0.10±0.007 μ M for L ‐deprenyl. Moreover, mouse brain MAO‐B activity was 90% ex vivo inhibited by both compounds 1 h after 4 mg kg −1 adminstration, MAO‐A activity was not affected. These novel molecules should provide a better understanding of the active site of monoamine oxidase and could be the starting point for the design of further selective, non‐amphetamine‐like MAO‐B inhibitors with therapeutic potential for the treatment of neurological disorders.British Journal of Pharmacology (1999) 127 , 869–876; doi: 10.1038/sj.bjp.0702600