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

[摘要] 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.

[发布机构] University:University of Birmingham;Department:School of Chemistry

[关键词] Q Science;QD Chemistry