Binding of rasagiline-related inhibitors to human monoamine oxidases: A kinetic and crystallographic analysis

Claudia Binda, Frantisek Hubálek, Min Li, Yaacov Herzig, Jeffrey Sterling, Dale E. Edmondson, Andrea Mattevi

Research output: Contribution to journalArticlepeer-review

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 Å 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. l(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.

Original languageEnglish (US)
Pages (from-to)8148-8154
Number of pages7
JournalJournal of medicinal chemistry
Volume48
Issue number26
DOIs
StatePublished - Dec 29 2005

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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