Evidence that the atypical 5‐HT3 receptor ligand, [3H]‐BRL46470, labels additional 5‐HT3 binding sites compared to [3H]‐granisetron

Steward, Lucinda J.; Jin, G.; Bentley, Kim R; Barber, P. C.; Hope, Anthony G.; Lambert, Jeremy J.; Peters, John A.; Blackburn, Thomas P.; Barnes, Nicholas M.

doi:10.1111/j.1476-5381.1995.tb16663.x

Cited by 28 publications

(2 citation statements)

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“…This is consistent with the previously reported subnanomolar WT-5-HT 3 A-receptor IC 50 ’s of ondansetron (e.g., 0.44 nM) . and granisetron (e.g., 0.2 nM) and slightly higher values for bemesetron (e.g., 30 nM or 0.77 μM) , Exploring the effects of some of these 5-HT 3 antagonists in ELIC revealed that they could also inhibit GABA-gated ELIC responses though at much higher concentrations; the IC 50 ’s of ondansetron and bemesetron were 0.63 ± 0.08 μM (mean ± SEM, n = 3) and 38 ± 9 μM (mean ± SEM, n = 3), respectively (Figure ).…”

Section: Resultssupporting

confidence: 91%

Characterization of a 5-HT₃–ELIC Chimera Revealing the Sites of Action of Modulators

Price

Lummis

2018

ACS Chem. Neurosci.

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Cys-loop receptors are major sites of action for many important therapeutically active compounds, but the sites of action of those that do not act at the orthosteric binding site or at the pore are mostly poorly understood. To help understand these, we here describe a chimeric receptor consisting of the extracellular domain of the 5-HTA receptor and the transmembrane domain of a prokaryotic homologue, ELIC. Alterations of some residues at the coupling interface are required for function, but the resulting receptor expresses well and responds to 5-HT with a lower EC (0.34 μM) than that of the 5-HTA receptor. Partial agonists and competitive antagonists of the 5-HTA receptor activate and inhibit the chimera as expected. Examination of a range of receptor modulators, including ethanol, thymol, 5-hydroxyindole, and 5-chloroindole, which can affect the 5-HTA receptor and ELIC, suggest that these compounds act via the transmembrane domain, except for 5-hydroxyindole, which can compete with 5-HT at the orthosteric binding site. The data throw further light on the importance of coupling interface in Cys-loop receptors and provide a platform for examining the mechanism of action of compounds that act in the extracellular domain of the 5-HTA receptor and the transmembrane domain of ELIC.

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Section: Resultssupporting

confidence: 91%

Characterization of a 5-HT₃–ELIC Chimera Revealing the Sites of Action of Modulators

Price

Lummis

2018

ACS Chem. Neurosci.

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“…In addition, palonosetron evokes some receptor internalization that is less apparent with ondansetron and granisetron (Rojas et al ., ). Another atypical 5‐HT 3 receptor antagonist, , has an enhanced binding capacity to recombinant 5‐HT 3 A receptors (Steward et al ., ). However, in the present study both palonosetron and behaved as other ‘classical’ 5‐HT 3 receptor antagonists (alosetron, ondansetron, ramosetron) by not displaying agonist activity even in the presence of a maximal concentration of Cl‐indole as assessed by measurements of intracellular calcium in HEKh5‐HT3A cells.…”

Section: Discussionmentioning

confidence: 97%

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

Batis

Grafton

Caputo

et al. 2013

British J Pharmacology

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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:

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Binding characteristics of GYKI-46 903, a non-competitive ligand at 5-HT3receptors

Vitalis¹,

Sebestyén²,

Sike³

et al. 2001

Pharmacological Research

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Evidence that the atypical 5‐HT₃ receptor ligand, [³H]‐BRL46470, labels additional 5‐HT₃ binding sites compared to [³H]‐granisetron

Cited by 28 publications

References 28 publications

Characterization of a 5-HT₃–ELIC Chimera Revealing the Sites of Action of Modulators

Characterization of a 5-HT₃–ELIC Chimera Revealing the Sites of Action of Modulators

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

Binding characteristics of GYKI-46 903, a non-competitive ligand at 5-HT3receptors

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Evidence that the atypical 5‐HT3 receptor ligand, [3H]‐BRL46470, labels additional 5‐HT3 binding sites compared to [3H]‐granisetron

Cited by 28 publications

References 28 publications

Characterization of a 5-HT3–ELIC Chimera Revealing the Sites of Action of Modulators

Characterization of a 5-HT3–ELIC Chimera Revealing the Sites of Action of Modulators

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

Binding characteristics of GYKI-46 903, a non-competitive ligand at 5-HT3receptors

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Product

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Evidence that the atypical 5‐HT₃ receptor ligand, [³H]‐BRL46470, labels additional 5‐HT₃ binding sites compared to [³H]‐granisetron

Characterization of a 5-HT₃–ELIC Chimera Revealing the Sites of Action of Modulators

Characterization of a 5-HT₃–ELIC Chimera Revealing the Sites of Action of Modulators

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