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
5‐Chloroindole: a potent allosteric modulator of the 5‐HT3 receptor
Sie können Bookmarks mittels Listen verwalten, loggen Sie sich dafür bitte in Ihr SLUB Benutzerkonto ein.
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:
0007-1188;
1476-5381
Entstehung:
Anmerkungen:
Beschreibung:
Background and PurposeThe 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.Experimental Approach5‐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.Key ResultsCl‐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 and ImplicationsThe 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.Linked ArticlesRecent reviews on allosteric modulation can be found at: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.xRoche 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