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Evidence for a cyanine link between propargylamine drugs and monoamine oxidase clarifies the inactivation mechanism

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Date
28/05/2018
Author
Albreht, Alen
Vovk, Irena
Mavri, Janez
Marco-Contelles, Jose
Ramsay, Rona R.
Funder
The Royal Society of Edinburgh
Grant ID
N/A
Keywords
Monoamine oxidase
Propargylamine
Inhibition mechanism
Electrostatic interactions
Quantum chemical calculations
Isomers
Interconversion
Structure
QD Chemistry
RM Therapeutics. Pharmacology
NDAS
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Abstract
Successful propargylamine drugs such as deprenyl inactivate monoamine oxidase (MAO), a target in multi-faceted approaches to prevent neurodegeneration in the aging population, but the chemical structure and mechanism of the irreversible inhibition are still debated. We characterized the covalent cyanine structure linking the multi-target propargylamine inhibitor ASS234 and the flavin adenine dinucleotide in MAO-A using a combination of ultra-high performance liquid chromatography, spectroscopy, mass spectrometry, and computational methods. The partial double bond character of the cyanine chain gives rise to 4 interconverting geometric isomers of the adduct which were chromatographically separated at low temperatures. The configuration of the cyanine linker governs adduct stability with segments of much higher flexibility and rigidity than previously hypothesized. The findings indicate the importance of intramolecular electrostatic interactions in the MAO binding site and provide key information relevant to incorporation of the propargyl moiety into novel multi-target drugs. Based on the structure, we propose a mechanism of MAO inactivation applicable to all propargylamine inhibitors.
Citation
Albreht , A , Vovk , I , Mavri , J , Marco-Contelles , J & Ramsay , R R 2018 , ' Evidence for a cyanine link between propargylamine drugs and monoamine oxidase clarifies the inactivation mechanism ' , Frontiers in Chemistry , vol. 6 , 169 . https://doi.org/10.3389/fchem.2018.00169
Publication
Frontiers in Chemistry
Status
Peer reviewed
DOI
https://doi.org/10.3389/fchem.2018.00169
ISSN
2296-2646
Type
Journal article
Rights
Copyright © 2018 Albreht, Vovk, Mavri, Marco-Contelles and Ramsay. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Description
The authors acknowledge the financial support from the Slovenian Research Agency (research core funding No. P1-0005 and P1-0012). We thank COST CA15135 for facilitating collaboration on multi-target compounds and providing support for publication. Part of this work was also supported by the bilateral cooperation between the Royal Society of Edinburgh and the Slovenian Academy of Sciences and Arts and by COST Action CM1103 which facilitated short research visits in Ljubljana and St Andrews, respectively.
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  • University of St Andrews Research
URI
http://hdl.handle.net/10023/13554

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