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Title: Chemical biology tools for ion channel drug discovery
Author: Raymond, Philip Neil
ISNI:       0000 0004 9356 6221
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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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.
Supervisor: Armstrong, Alan ; Okuse, Kenji Sponsor: Engineering and Physical Sciences Research Council ; Pfizer Ltd
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral