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PDBsum entry 2c67
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Oxidoreductase
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PDB id
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2c67
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References listed in PDB file
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Key reference
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Title
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Binding of rasagiline-Related inhibitors to human monoamine oxidases: a kinetic and crystallographic analysis.
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Authors
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C.Binda,
F.Hubálek,
M.Li,
Y.Herzig,
J.Sterling,
D.E.Edmondson,
A.Mattevi.
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Ref.
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J Med Chem, 2005,
48,
8148-8154.
[DOI no: ]
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PubMed id
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Abstract
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Monoamine oxidases A and B (MAO A and B) catalyze the degradation of
neurotransmitters and represent drug targets for the treatment of
neurodegenerative disorders. Rasagiline is an irreversible, MAO B-selective
inhibitor that has been approved as a novel anti-Parkinson's drug. In this
study, we investigate the inhibition of recombinant human MAO A and MAO B by
several rasagiline analogues. Different substituents added onto the rasagiline
scaffold alter the binding affinity depending on the position on the aminoindan
ring and on the size of the substituent. Compounds with a hydroxyl group on
either the C4 or the C6 atom inhibit both isozymes, whereas a bulkier
substituent such as a carbamate is tolerated only at the C4 position. The 1.7 A
crystal structure of MAO B in complex with
4-(N-methyl-N-ethyl-carbamoyloxy)-N-methyl-N-propargyl-1(R)-aminoindan shows
that the binding mode is similar to that of rasagiline with the carbamate moiety
occupying the entrance cavity space. 1(R)-Aminoindan, the major metabolic
product of rasagiline, and its analogues reversibly inhibit both MAO A and MAO
B. The crystal structure of N-methyl-1(R)-aminoindan bound to MAO B shows that
its aminoindan ring adopts a different orientation compared to that of
rasagiline.
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