The modulation of Transient Receptor Potential A1 channel by natural and novel semi-synthetic compounds via non-covalent modification

Knaggs, Jonathan David

September 2016

Thesis or dissertation

© 2016 Jonathan David Knaggs. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.

Transient Receptor Potential A1 (TRPA1) is commonly known as the detector of a broad range of noxious chemical agents both exogenous and endogenous. TRPA1 detects these chemicals through a reversible covalent modification mechanism that allows most electrophilic compounds to activate the channel; hence one of the channel’s key roles is to protect the respiratory system from harmful irritants by activating the cough reflex. It has been proposed that TRPA1 is involved in chronic inflammatory diseases of the respiratory system and has been highlighted as a potential drug target for this as well as general pain and inflammation.

TRPA1 is also activated by non-covalent mechanisms, which are less well understood. I therefore aimed to gain a further understanding of non-covalent mechanisms of TRPA1 modulation via structure-activity relationship studies using several groups of diverse compounds based on existing TRPA1 agonists.

The results reported have shown that compounds based on thymol, carvacrol and fenamic acid have a diverse effect on TRPA1 dependent on small alterations in structure. This highlights the delicate nature of the TRPA1 non-covalent binding sites. The derivatives tested all share one common structural feature; they all have two phenyl rings which are linked via different functional groups and different lengths. It was found that the length of the linker had an effect on the potency of the modulation of TRPA1. In addition to these results NDGA and its semi-synthetic derivative M4N were potent TRPA1 agonists, yet unlike other similar compounds do not desensitise TRPA1, possibly due to their folded structure. Throughout the results, the importance of hydrogen bonding was shown with different functional groups capable of acting as donors or acceptors.

Overall the results reported expand the group of non-covalent modulators of TRPA1 and indicated important structural features that must be considered in any future TRPA1 drug development projects.

Hull York Medical School, The University of Hull and University of York
Sadofsky, Laura R.; Boa, Andrew
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