The effect of side chain substitution at positions 2 and 3 of the heterocyclic ring of N-acetylenic analogues of tryptamine as monoamine oxidase inhibitors.
N-Acetylenic analogues of tryptamine in which the side chain is located at position 2 of the indole ring are compared with those in which the side chain is located at position 3, in terms of their actions as inhibitors of monoamine oxidases A and B. IC50 values at 0 and 30 min of pre-incubation were determined. Time-dependence and irreversible inhibition confirmed that all of them behave as mechanism-based inhibitors. The kinetic constants of each inhibition step were determined for both monoamine oxidase forms and compared between them. In all cases the first-order rate constants for the covalent adduct formation were similar to inhibitor selectivity which is derived solely from differences in affinities for non-covalent binding to the A and B enzymes. Those compounds where the acetylenic side chain was substituted at position 2 of the heterocyclic ring and selective inhibitors of monoamine oxidase A were more potent than those with the side chain in position 3.
Department Bioquímica i Biologia Molecular Faculty, Medicina Universitat Autónoma de Barcelona, Spain.
M
M
Avila
M D
MD
Balsa
E
E
Fernandez-Alvarez
K F
KF
Tipton
M
M
Unzeta
D000114:Acetylene / Q000031:analogs & derivatives; D000818:Animals; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014363:Tryptamines / Q000737:chemistry*
D008996:Monoamine Oxidase Inhibitors; D014363:Tryptamines; C030820:tryptamine; D000114:Acetylene