Chemical biology tools for ion channel drug discovery
File(s)
Author(s)
Raymond, Philip Neil
Type
Thesis
Abstract
Ion channels are important therapeutic targets for drug discovery. Voltage Gated Sodium Channels (VGSCs), for example, are involved in the treatment of chronic pain, epilepsy and cardiac arrhythmia, amongst other conditions. However, drugs, chemical probes and other small molecule imhibitors used to investigate or modulate them are typically unselective between VSGC subtypes, and other ion channels. The research described in this thesis develops chemical methodology that will allow for greater insight into the subtype-selective structure, function and modulation of these proteins, with a particular emphasis on VGSCs implicated in pain pathways.
The first chapter describes the development of novel methodology for the synthesis of vinyl sulfonamides, an electrophilic class of molecules that can be used in the affinity labelling of a variety of classes of ion channel, including some of those involved in pain pathways. The second chapter describes the development of photoaffinity labelling probes in an attempt to define the binding site of a subtype-selective series of inhibitors of NaV1.8, a VGSC found in the peripheral nervous system strongly implicated in the transmission of pain. It then goes on to develop a hypothesis for the mechanism behind this subtype-selectivity by combining computational modelling with information gained in the development of the aforementioned probes. The final chapter moves from the structure to the function of the channels, describing early work towards synthesising subtype-selective photocaged tools, with which the function of NaV1.8 could be explored with spatial and temporal precision. In this context, it also explores the question of whether or not meso-methyl substituted BODIPY compounds can be used as photocaging groups for amides.
The first chapter describes the development of novel methodology for the synthesis of vinyl sulfonamides, an electrophilic class of molecules that can be used in the affinity labelling of a variety of classes of ion channel, including some of those involved in pain pathways. The second chapter describes the development of photoaffinity labelling probes in an attempt to define the binding site of a subtype-selective series of inhibitors of NaV1.8, a VGSC found in the peripheral nervous system strongly implicated in the transmission of pain. It then goes on to develop a hypothesis for the mechanism behind this subtype-selectivity by combining computational modelling with information gained in the development of the aforementioned probes. The final chapter moves from the structure to the function of the channels, describing early work towards synthesising subtype-selective photocaged tools, with which the function of NaV1.8 could be explored with spatial and temporal precision. In this context, it also explores the question of whether or not meso-methyl substituted BODIPY compounds can be used as photocaging groups for amides.
Version
Open Access
Date Issued
2017-12
Date Awarded
2018-08
Advisor
Armstrong, Alan
Okuse, Kenji
Sponsor
Engineering and Physical Sciences Research Council
Pfizer Ltd.
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)