Binding of rasagiline-related inhibitors to human monoamine oxidases. a kinetic and crystallographic analysis

被引:94
作者
Binda, C
Hubálek, F
Li, M
Herzig, Y
Sterling, J
Edmondson, DE
Mattevi, A
机构
[1] Univ Pavia, Dept Genet & Microbiol, I-27100 Pavia, Italy
[2] Emory Univ, Dept Biochem, Atlanta, GA 30322 USA
[3] Emory Univ, Dept Chem, Atlanta, GA 30322 USA
[4] Teva Pharmaceut Ind, Div Res & Dev, Netanya, Israel
关键词
D O I
10.1021/jm0506266
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 angstrom crystal structure of MAO B in complex with 4-(N-methyl-N-ethyl-carbamoyloxy)-Nmethyl-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 XIAO 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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页码:8148 / 8154
页数:7
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