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Title: Investigation of the allosteric pharmacology of the 5-HT₃ receptor identifying the potent allosteric modulator 5-chloroindole
Author: Batis, Nikolaos
ISNI:       0000 0004 5351 5964
Awarding Body: University of Birmingham
Current Institution: University of Birmingham
Date of Award: 2015
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The 5-HT₃ receptor is a ligand-gated ion channel that mediates for example fast synaptic neurotransmission in the CNS and PNS. 5-HT₃ receptor antagonists are established anti-emetics in the clinic, they also offer symptomatic relief for patients with irritable bowel syndrome, yet, sometimes serious side-effects limits their use in this indication. The 5-HT₃ receptor is modulated allosterically by various compounds including colchicine, alcohols and volatile anaesthetics but as yet, these modulators either lack potency or selectivity, which hinders investigation. The present study reports a novel 5-HT₃ receptor allosteric modulator that displays relatively high potency and selectivity; 5-chloro-indole (Cl-indole). Cl-indole potentiated 5-HT₃ receptor mediated responses arising from heterologous expression of the h5-HT₃A receptor (assessed by the affinity shift of agonists to compete for the radioligand binding site and by the increase in agonist action upon the h5-HT₃A receptor-mediated increase in [Ca²⁺]i; the latter action was evident with a range of agonists with very low intrinsic activity to full agonists). Cl-indole was also able to modulate allosterically the mouse native 5-HT₃ receptor. Additional studies provided further support for the role of the C-terminus of the h5-HT₃A subunit to promote stability of the arising 5-HT₃ receptor complex and that ligand interaction with the 5-HT₃A receptor impacted cell surface expression. In summary, the study reports the identification of Cl-indole as a positive allosteric modulator of the 5-HT₃ receptor along with extensions to our knowledge concerning a structural component of the 5-HT₃A subunit that promotes stability and the trafficking of the subunit into the cell membrane. These studies increase our understanding of the 5-HT₃ receptor, which may contribute to the design of better drugs targeting this receptor for therapeutic benefit.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RM Therapeutics. Pharmacology