5‐Chloroindole: a potent allosteric modulator of the 5‐HT3 receptor

Medientyp: E-Artikel
Titel: 5‐Chloroindole: a potent allosteric modulator of the 5‐HT3 receptor
Beteiligte: 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
Erschienen: Wiley, 2013
Erschienen in: British Journal of Pharmacology, 169 (2013) 6, Seite 1228-1238
Sprache: Englisch
DOI: 10.1111/bph.12213
ISSN: 1476-5381; 0007-1188
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Beschreibung: <jats:sec><jats:title>Background and Purpose</jats:title><jats:p>The 5‐<jats:styled-content style="fixed-case">HT</jats:styled-content><jats:sub>3</jats: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 (<jats:styled-content style="fixed-case">PAMs</jats:styled-content>) identified to date have low affinity, which hinders investigation because of non‐selective effects at pharmacologically active concentrations. The present study identifies 5‐chloroindole (<jats:styled-content style="fixed-case">C</jats:styled-content>l‐indole) as a potent <jats:styled-content style="fixed-case">PAM</jats:styled-content> of the 5‐<jats:styled-content style="fixed-case">HT</jats:styled-content><jats:sub>3</jats:sub> receptor.</jats:p></jats:sec><jats:sec><jats:title>Experimental Approach</jats:title><jats:p>5‐<jats:styled-content style="fixed-case">HT</jats:styled-content><jats:sub>3</jats:sub> receptor function was assessed by the increase in intracellular calcium and single‐cell electrophysiological recordings in <jats:styled-content style="fixed-case">HEK</jats:styled-content>293 cells stably expressing the h5‐<jats:styled-content style="fixed-case">HT</jats:styled-content><jats:sub>3</jats:sub><jats:styled-content style="fixed-case">A</jats:styled-content> receptor and also the mouse native 5‐<jats:styled-content style="fixed-case">HT</jats:styled-content><jats:sub>3</jats:sub> receptor that increases neuronal contraction of bladder smooth muscle.</jats:p></jats:sec><jats:sec><jats:title>Key Results</jats:title><jats:p>Cl‐indole (1–100 μ<jats:styled-content style="fixed-case">M</jats:styled-content>) potentiated agonist (5‐<jats:styled-content style="fixed-case">HT</jats:styled-content>) and particularly partial agonist [(<jats:styled-content style="fixed-case">S</jats:styled-content>)‐zacopride, <jats:styled-content style="fixed-case">DDP</jats:styled-content>733, <jats:styled-content style="fixed-case">RR</jats:styled-content>210, quipazine, dopamine, 2‐methyl‐5‐<jats:styled-content style="fixed-case">HT</jats:styled-content>, <jats:styled-content style="fixed-case">SR</jats:styled-content>57227<jats:styled-content style="fixed-case">A</jats:styled-content>, <jats:italic>meta</jats:italic> chlorophenyl biguanide] induced h5‐<jats:styled-content style="fixed-case">HT</jats:styled-content><jats:sub>3</jats:sub><jats:styled-content style="fixed-case">A</jats:styled-content> receptor‐mediated responses. This effect of <jats:styled-content style="fixed-case">C</jats:styled-content>l‐indole was also apparent at the mouse native 5‐<jats:styled-content style="fixed-case">HT</jats:styled-content><jats:sub>3</jats:sub> receptor. Radioligand‐binding studies identified that <jats:styled-content style="fixed-case">C</jats:styled-content>l‐indole induced a small (∼twofold) increase in the apparent affinity of 5‐<jats:styled-content style="fixed-case">HT</jats:styled-content> for the h5‐<jats:styled-content style="fixed-case">HT</jats:styled-content><jats:sub>3</jats:sub><jats:styled-content style="fixed-case">A</jats:styled-content> receptor, whereas there was no effect upon the affinity of the antagonist, tropisetron. <jats:styled-content style="fixed-case">C</jats:styled-content>l‐indole was able to reactivate desensitized 5‐<jats:styled-content style="fixed-case">HT</jats:styled-content><jats:sub>3</jats:sub> receptors. In contrast to its effect on the 5‐<jats:styled-content style="fixed-case">HT</jats:styled-content><jats:sub>3</jats:sub> receptor, <jats:styled-content style="fixed-case">C</jats:styled-content>l‐indole did not alter human nicotinic α7 receptor responses.</jats:p></jats:sec><jats:sec><jats:title>Conclusions and Implications</jats:title><jats:p>The present study identifies <jats:styled-content style="fixed-case">C</jats:styled-content>l‐indole as a relatively potent and selective <jats:styled-content style="fixed-case">PAM</jats:styled-content> of the 5‐<jats:styled-content style="fixed-case">HT</jats:styled-content><jats:sub>3</jats:sub> receptor; such compounds will aid investigation of the molecular basis for allosteric modulation of the 5‐<jats:styled-content style="fixed-case">HT</jats:styled-content><jats:sub>3</jats:sub> receptor and may assist the discovery of novel therapeutic drugs targeting this receptor.</jats:p></jats:sec><jats:sec><jats:title>Linked Articles</jats:title><jats:p>Recent reviews on allosteric modulation can be found at:</jats:p><jats: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</jats:p><jats: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</jats:p></jats:sec>
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