title: Binding of rasagiline-related inhibitors to human monoamine oxidases: a kinetic and crystallographic analysis.
abstract: 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.
authors.affiliation: Department of Genetics and Microbiology, University of Pavia, via Abbiategrasso 207, Pavia 27100 Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Binda
authors.forename: Frantisek
authors.initials: F
authors.lastname: Hubálek
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Yaacov
authors.initials: Y
authors.lastname: Herzig
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Sterling
authors.forename: Dale E
authors.initials: DE
authors.lastname: Edmondson
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattevi
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D007189:Indans / Q000737:chemistry; D007700:Kinetics; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
chemical_list: D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D011994:Recombinant Proteins; C031967:rasagiline; D008995:Monoamine Oxidase