5‐Chloroindole: a potent allosteric modulator of the 5‐HT3 receptor. (21st June 2013)

• Record Type: Journal Article
• Authors: Newman, Amy S; Batis, Nikolaos; Grafton, Gillian; Caputo, Francesca; Brady, Catherine A; Lambert, Jeremy J; Peters, John A; Gordon, John; Brain, Keith L; Powell, Andrew D; Barnes, Nicholas M
• Is Part Of: British journal of pharmacology. Volume 169:Number 6(2013:Jul.)
• Page Start: 1228
• Page End: 1238
• Publication Date: 2013-06-21
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12213
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12213-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>The 5‐HT<sub>3</sub> 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‐HT<sub>3</sub> receptor.</p> </sec> <sec id="bph12213-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>5‐HT<sub>3</sub> receptor function was assessed by the increase in intracellular calcium and single‐cell electrophysiological recordings in HEK293 cells stably expressing the h5‐HT<sub>3</sub>A receptor and also the mouse native 5‐HT<sub>3</sub> receptor that increases neuronal contraction of bladder smooth muscle.</p> </sec> <sec id="bph12213-sec-0003" sec-type="section"> <title>Key Results</title> <p>Cl‐indole (1–100 μM) potentiated agonist (5‐HT) and particularly partial agonist [(S)‐zacopride, DDP733, RR210, quipazine, dopamine, 2‐methyl‐5‐HT, SR57227A, <italic>meta</italic> chlorophenyl biguanide] induced h5‐HT<sub>3</sub>A receptor‐mediated responses. This effect of Cl‐indole was also apparent at the mouse native 5‐HT<sub>3</sub> receptor. Radioligand‐binding studies identified that Cl‐indole induced a small (∼twofold) increase in the apparent affinity of 5‐HT for the h5‐HT<sub>3</sub>A receptor, whereas there was no effect upon the affinity of the antagonist, tropisetron. Cl‐indole was able to reactivate desensitized 5‐HT<sub>3</sub> receptors. In contrast to its effect on the 5‐HT<sub>3</sub> receptor, Cl‐indole did not alter human nicotinic α7 receptor responses.</p> </sec> <sec id="bph12213-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>The present study identifies Cl‐indole as a relatively potent and selective PAM of the 5‐HT<sub>3</sub> receptor; such compounds will aid investigation of the molecular basis for allosteric modulation of the 5‐HT<sub>3</sub> receptor and may assist the discovery of novel therapeutic drugs targeting this receptor.</p> </sec> <sec id="bph12231-sec-5001" sec-type="relatedArticles"> <title>Linked Articles</title> <p>Recent reviews on allosteric modulation can be found at:</p> <p>Kenakin, T (2013). New concepts in pharmacological efficacy at 7TM receptors: IUPHAR Review 2. British Journal of Pharmacology 168: 554–575. doi: 10.1111/j.1476‐5381.2012.02223.x</p> <p>Roche D, Gil D and Giraldo J (2013). Mechanistic analysis of the function of agonists and allosteric modulators: reconciling two‐state and operational models. British Journal of Pharmacology 169: 1189–1202. doi: 10.1111/bph.12231</p> </sec> </abstract>