1 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. 2 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. 3 The K i values for MAO-A and MAO-B were 800+60 and 0.75+0.15 nM, 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 nM for MAO A and MAO-B, respectively). The IC 50 values for dopamine uptake in striatal synaptosomal fractions from rats were 150+8 mM for FA-73 and 68+10 mM for L-deprenyl whereas in human caudate tissue the IC 50 values were 0.36+0.015 mM for FA-73 and 0.10+0.007 mM for L-deprenyl. Moreover, mouse brain MAO-B activity was 90% ex vivo inhibited by both compounds 1 h after 4 mg kg 71 adminstration, MAO-A activity was not a ected. 4 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.
Some fused 5H-pyridazino[4,5-b]indoles (7-10), substituted in positions 1 and 4 by hydrazine and/or amino groups, have been synthesized. These new compounds present a planar topography, a dipole with an adjacent acidic proton, and a basic hydrogen-acceptor site opposite the dipole. These compounds have some resemblance to carbazeram and other pyridazino agents with cardiotonic activity. Some of the new compounds here described possess inotropic activity (Table I and II), with a complementary effect as inhibitors of platelet aggregation (Table III and IV). 1-Hydrazino-4-(3,5-dimethyl)-1-pyrazolyl-5H-pyridazino[4,5-b ]indole hydrochloride (7a.HCl) is the first compound described in the literature with activities as inhibitor of PDE-IV and as selective inhibitor of TXA2 synthetase (Table V).
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.