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Selective allosteric modulation of the 5‐HT3A receptor by halogenated indole derivates
Author(s) -
Barnes Nicholas,
Chiarenza Alessandra,
Gambassi Silvia,
Powell Andrew,
Grafton Gillian
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1174.2
Subject(s) - allosteric regulation , allosteric modulator , receptor , radioligand , chemistry , 5 ht3 receptor , pharmacology , nicotinic agonist , biophysics , biochemistry , biology , 5 ht receptor , serotonin
The human 5‐HT3A receptor is a member of the cys‐loop ligand‐gated ion channel family. Allosteric modulators of this receptor have potential roles in the treatment of irritable bowel syndrome. In the present study we have used radioligand binding assays, fluorescence indicators and patch clamp techniques to explore the allosteric modulation of human 5‐HT3A stably expressed in HEK293 cells. We examined a range of halogenated indole derivatives and discovered seven novel positive allosteric modulators (PAMs) of the 5‐HT3 receptor, of which two were examined in more detail. Radioligand binding assays showed that neither 5‐chloroindole nor 5‐iodoindole (up to 100 μM) competed with [3H]‐granisetron for the 5‐HT3A receptor orthosteric site or affected the affinity of ondansetron for the receptor. In contrast both molecules provoked an increase in the affinity of several agonists/partial agonists for the receptor. Importantly, there was no effect on human nicotinic alpha 7 receptor mediated responses, unlike previously described PAMs at the 5‐HT3A receptor, allowing the use of 5‐HT3A/nicotinic alpha‐7 chimeras to map the binding site(s) for these molecules. Such studies will aid rational design of useful therapeutic agents that modulate 5‐HT3 receptor function.