Investigation of the allosteric pharmacology of the 5-HT $_3$ receptor identifying the potent allosteric modulator 5-chloroindole

Batis, Nikolaos (2015). Investigation of the allosteric pharmacology of the 5-HT $_3$ receptor identifying the potent allosteric modulator 5-chloroindole. University of Birmingham. Ph.D.

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Abstract

The 5-HT $_3$ receptor is a ligand-gated ion channel that mediates for example fast synaptic neurotransmission in the CNS and PNS. 5-HT $_3$ 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-HT $_3$ 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-HT $_3$ receptor allosteric modulator that displays relatively high potency and selectivity; 5-chloro-indole (Cl-indole). Cl-indole potentiated 5-HT $_3$ receptor mediated responses arising from heterologous expression of the h5-HT $_3$ A 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-HT $_3$ A receptor-mediated increase in [Ca $^2$ $^+$ ]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-HT $_3$ receptor.

Additional studies provided further support for the role of the C-terminus of the h5-HT $_3$ A subunit to promote stability of the arising 5-HT $_3$ receptor complex and that ligand interaction with the 5-HT $_3$ A receptor impacted cell surface expression.

In summary, the study reports the identification of Cl-indole as a positive allosteric modulator of the 5-HT $_3$ receptor along with extensions to our knowledge concerning a structural component of the 5-HT $_3$ A subunit that promotes stability and the trafficking of the subunit into the cell membrane. These studies increase our understanding of the 5-HT $_3$ receptor, which may contribute to the design of better drugs targeting this receptor for therapeutic benefit.