title: 5-Chloroindole: a potent allosteric modulator of the 5-HT₃ receptor.
abstract: OBJECTIVE
  The 5-HT₃ receptor is a ligand-gated ion channel that is modulated allosterically by various compounds including colchicine, alcohols and volatile anaesthetics. However the positive allosteric modulators (PAMs) identified to date have low affinity, which hinders investigation because of non-selective effects at pharmacologically active concentrations. The present study identifies 5-chloroindole (Cl-indole) as a potent PAM of the 5-HT₃ receptor.
  
  
  METHODS
  5-HT₃ receptor function was assessed by the increase in intracellular calcium and single-cell electrophysiological recordings in HEK293 cells stably expressing the h5-HT₃A receptor and also the mouse native 5-HT₃ receptor that increases neuronal contraction of bladder smooth muscle.
  
  
  RESULTS
  Cl-indole (1-100 μM) potentiated agonist (5-HT) and particularly partial agonist [(S)-zacopride, DDP733, RR210, quipazine, dopamine, 2-methyl-5-HT, SR57227A, meta chlorophenyl biguanide] induced h5-HT₃A receptor-mediated responses. This effect of Cl-indole was also apparent at the mouse native 5-HT₃ receptor. Radioligand-binding studies identified that Cl-indole induced a small (≈ twofold) increase in the apparent affinity of 5-HT for the h5-HT₃A receptor, whereas there was no effect upon the affinity of the antagonist, tropisetron. Cl-indole was able to reactivate desensitized 5-HT₃ receptors. In contrast to its effect on the 5-HT₃ receptor, Cl-indole did not alter human nicotinic α7 receptor responses.
  
  
  CONCLUSIONS
  The present study identifies Cl-indole as a relatively potent and selective PAM of the 5-HT₃ receptor; such compounds will aid investigation of the molecular basis for allosteric modulation of the 5-HT₃ receptor and may assist the discovery of novel therapeutic drugs targeting this receptor.
authors.affiliation: Cellular and Molecular Neuropharmacology Research Group, Clinical and Experimental Medicine, Medical School, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Newman
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Batis
authors.forename: Gillian
authors.initials: G
authors.lastname: Grafton
authors.forename: Francesca
authors.initials: F
authors.lastname: Caputo
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Brady
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Lambert
authors.forename: John A
authors.initials: JA
authors.lastname: Peters
authors.forename: John
authors.initials: J
authors.lastname: Gordon
authors.forename: Keith L
authors.initials: KL
authors.lastname: Brain
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Powell
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Barnes
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D054333:Drug Partial Agonism; D005071:Evoked Potentials / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009119:Muscle Contraction / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011985:Receptors, Serotonin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D058827:Serotonin 5-HT3 Receptor Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects
chemical_list: C000591389:5-chloroindole; C509409:HTR3A protein, human; D007211:Indoles; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D011994:Recombinant Proteins; D058827:Serotonin 5-HT3 Receptor Agonists; D058831:Serotonin 5-HT3 Receptor Antagonists