Palandri, Josephine C. (2015). An investigation into the effects of allosteric modulators of the human 5-Ht3A receptor. University of Birmingham. M.Sc.
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Palandri15MScbyRes.pdf
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Abstract
The 5-Ht3A receptor is a cys-loop ligand gated ion channel re-emerging as an attractive target in irritable bowel syndrome (IBS), which currently affects 5-10% of the global population. At present, IBS therapies involve the complete blockade of the 5-Ht3A receptor by orthosteric antagonists, which leads to complications such as severe constipation and ischaemic colitis. Allosteric modulation could bypass such side effects, as receptor function relies upon the endogenous neurotransmitter to retain physiological control. Here, we investigate the structure and function of the 5-Ht3A receptor allosteric binding site by the identification of novel allosteric compounds and the generation of an α7/5-HT3A chimeric receptor. Intracellular calcium assays and competitive radioligand binding experiments indicated that the halogenated indole derivatives, 5-chloroindole (5-Cl) (Newman et al., 2013) and 5- (trifluoromethyl)indole (5-TFMI) are positive allosteric modulators (PAM) of the 5-Ht3A receptor; however 5-TFMI also displayed a degree of orthosteric binding. The structural analogues, 5-bromoindazole (5-BI) and 5-bromo-benzimidazole (5-BBI) exhibited contrasting effects, by potentiating and decreasing 5-HT-evoked responses, respectively. Further studies suggested some orthosteric binding by 5-BI and 5-BBI at high concentrations. The allosteric binding site for 5-Cl was previously located in the N-terminus of the mouse 5-Ht3A receptor. To identify the site in the human receptor, we attempted to construct a human chimeric α7V2015-HT3A receptor to allow further investigation into this question. Our data suggest these halogenated indoles are allosteric compounds and, when studied in combination with the α7V2015-HT3A chimera, could identify the required core structure of high affinity compounds needed for negative allosteric modulation in the treatment of IBS.
| Type of Work: | Thesis (Masters by Research > M.Sc.) | |||||||||
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| Award Type: | Masters by Research > M.Sc. | |||||||||
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| College/Faculty: | Colleges (2008 onwards) > College of Medical & Dental Sciences | |||||||||
| School or Department: | School of Clincal and Experimental Medicine, Department of Pharmacology and Therapeutics | |||||||||
| Funders: | None/not applicable | |||||||||
| Subjects: | R Medicine > RM Therapeutics. Pharmacology | |||||||||
| URI: | http://etheses.bham.ac.uk/id/eprint/6287 |
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