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Kinetics, mechanism and inhibition of monoamine oxidase

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Ramsay_2018_Kinetics_JNT_AAM.pdf (677.7Kb)
Date
11/2018
Author
Ramsay, Rona R.
Albreht, Alen
Funder
European Commission
Grant ID
oc-2010-2-8526
Keywords
Enzyme kinetics
Irreversible inhibition
Multi-target drug design
Monoamine neurotransmitters
Computation and modelling
Chemical mechanism
QD Chemistry
QH301 Biology
RM Therapeutics. Pharmacology
Chemistry(all)
Analytical Chemistry
Biochemistry
Drug Discovery
Metadata
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Abstract
Monoamine oxidases (MAOs) catalyse the oxidation of neurotransmitter amines and a wide variety of primary, secondary and tertiary amine xenobiotics, including therapeutic drugs. While inhibition of MAO activity in the periphery removes protection from biogenic amines and so is undesirable, inhibition in the brain gives vital anti-depressant and behavioural advantages that make MAO a major pharmaceutical target for inhibitor design. In neurodegenerative diseases, MAO inhibitors can help maintain neurotransmitter levels, making it a common feature in novel multi-target combinations designed to combat Alzheimer’s disease, albeit not yet proven clinically. Vital information for inhibitor design comes from an understanding of the structure, mechanism and kinetics of the catalyst. This review will summarize the kinetic behaviour of MAO A and B and the kinetic evaluation of reversible inhibitors that transiently decrease catalysis. Kinetic parameters and crystal structures have enabled computational approaches to ligand discovery and validation of hits by docking. Kinetics and a wide variety of substrates and inhibitors along with theoretical modeling have also contributed to proposed schemes for the still debated chemical mechanism of amine oxidation, However, most of the marketed MAO drugs are long-lasting irreversible inactivators. The mechanism of irreversible inhibition by hydrazine, cyclopropylamine and propargylamine drugs will be discussed. The article finishes with some examples of the propargylamine moiety in multi-target ligand design to combat neurodegeneration.
Citation
Ramsay , R R & Albreht , A 2018 , ' Kinetics, mechanism and inhibition of monoamine oxidase ' , Journal of Neural Transmission , vol. 125 , no. 11 , pp. 1659–1683 . https://doi.org/10.1007/s00702-018-1861-9
Publication
Journal of Neural Transmission
Status
Peer reviewed
DOI
https://doi.org/10.1007/s00702-018-1861-9
ISSN
0300-9564
Type
Journal item
Rights
© 2018, Springer-Verlag GmbH Austria, part of Springer Nature. This work has been made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://doi.org/10.1007/s00702-018-1861-9
Description
Funding: EU COST Action CM1103.
Collections
  • University of St Andrews Research
URI
http://hdl.handle.net/10023/17231

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