The development of novel allosteric modulators of the 5-HT3A receptor

Myerson, Richard James (2017). The development of novel allosteric modulators of the 5-HT3A receptor. University of Birmingham. Ph.D.

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Abstract

This thesis reports the Structure Activity Relationship study that was performed upon the 5-substituted-indole core as a means to identify Negative Allosteric Modulators of the human 5-HT3A receptor for the development of potential drugs for the treatment of IBS-d. Herein is reported the successful identification of a PAM to NAM switch and three novel NAMs which provide the basis for further study into the treatment of IBS-d and insight into the identity of the allosteric site of the human 5-HT3A receptor. The design, synthesis and testing of a novel fluorescent analogue of the orthosteric antagonist Quipazine is also described for the application of an improved competitive binding experiment without the need for radio-labelled ligands. Furthermore, the design and synthesis of novel diazirinyl-indoles for photo-affinity binding studies towards the identification of the allosteric site of the 5-HT3A receptor. Finally, the design and synthesis of novel BODIPY-BAPTA based fluorescent PET sensors for the detection of larger than usual ranges in concentration of cellular Ca2+ levels are described.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):