Issue 39, 2019

Neurotransmitter selection by monoamine oxidase isoforms, dissected in terms of functional groups by mixed double mutant cycles

Abstract

Double mutant cycles were constructed using neurotransmitters and synthetic substrates that measure their selective binding to one monoamine oxidase (MAO) enzyme isoform over another as a function of structural change. This work measures a reduction in selectivity for the MAOB isoform of 3 to 9.5 kJ mol−1 upon the addition of hydroxy functional groups to a phenethylamine scaffold. Replacement of hydroxy functional groups on the phenethylamine scaffold by hydrophobic substituents measures an increase in selectivity for MAOB of −1.1 to −6.9 kJ mol−1. The strategies presented here can be applied to the development of competitive reversible inhibitors of MAO enzymes and other targets with structurally related isoforms.

Graphical abstract: Neurotransmitter selection by monoamine oxidase isoforms, dissected in terms of functional groups by mixed double mutant cycles

Supplementary files

Article information

Article type
Paper
Submitted
12 Jul 2019
Accepted
16 Sep 2019
First published
16 Sep 2019

Org. Biomol. Chem., 2019,17, 8871-8877

Neurotransmitter selection by monoamine oxidase isoforms, dissected in terms of functional groups by mixed double mutant cycles

L. Hudspith, F. Shmam, C. F. Dalton, A. Princivalle and S. M. Turega, Org. Biomol. Chem., 2019, 17, 8871 DOI: 10.1039/C9OB01558B

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