Interaction of indole derivatives with monoamine oxidase A and B. Studies on the structure-inhibitory activity relationship.
Indole and isatin (2,3-dioxindole) analogues were studied as inhibitors of MAO-A and B. They exhibited reversible and competitive MAO inhibition. Three dimensional structures of the compounds tested were constructed and minimized using PC-based molecular graphic software. The QSAR analysis revealed the requirement of co-planar structure of substituents at C2 and C3 of indole ring for selective MAO-A inhibition, whilst type of bond was less essential. The presence of hydroxy group at C5 of isatin increased selectivity of MAO-A inhibition, however simultaneous insertion of substituents into both positions of indole ring (5-hydroxy-2-phenylindole) led to a decrease of MAO-A inhibition. The planar molecules demonstrating potent MAO-A inhibition have the average sizes 7 A in length and 6 A in width. The MAO B inhibition also depended on the sizes of planar molecules however distribution of electron density in the molecules was another precondition for the selective inhibition of the enzyme.
Medvedev
A E
AE
Institute of Biomedical Chemistry, Russian Academy of Medical Sciences.
Ivanov
A S
AS
Kamyshanskaya
N S
NS
Kirkel
A Z
AZ
Moskvitina
T A
TA
Gorkin
V Z
VZ
Li
N Y
NY
Marshakov VYu
D000818:Animals; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007510:Isatin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D008928:Mitochondria / Q000201:enzymology*; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D007211:Indoles; D008996:Monoamine Oxidase Inhibitors; D007510:Isatin; D008995:Monoamine Oxidase