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Potentiation and allosteric agonist activation of α7 nicotinic acetylcholine receptors: binding sites and hypotheses

Sanders, Victoria R; Millar, Neil S; (2023) Potentiation and allosteric agonist activation of α7 nicotinic acetylcholine receptors: binding sites and hypotheses. Pharmacological Research , 191 , Article 106759. 10.1016/j.phrs.2023.106759. Green open access

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Abstract

Considerable progress has been made in recent years towards the identification and characterisation of novel subtype-selective modulators of nicotinic acetylcholine receptors (nAChRs). In particular, this has focussed on modulators of α7 nAChRs, a nAChR subtype that has been identified as a target for drug discovery in connection with a range of potential therapeutic applications. This review focusses upon α7-selective modulators that bind to receptor sites other than the extracellular 'orthosteric' agonist binding site for the endogenous agonist acetylcholine (ACh). Such compounds include those that are able to potentiate responses evoked by orthosteric agonists such as ACh (positive allosteric modulators; PAMs) and those that are able to activate α7 nAChRs by direct allosteric activation in the absence of an orthosteric agonist (allosteric agonists or 'ago-PAMs'). There has been considerable debate about the mechanism of action of α7-selective PAMs and allosteric agonists, much of which has centred around identifying the location of their binding sites on α7 nAChRs. Based on a variety of experimental evidence, including recent structural data, there is now clear evidence indicating that at least some α7-selective PAMs bind to an inter-subunit site located in the transmembrane domain. In contrast, there are differing hypotheses about the site or sites at which allosteric agonists bind to α7 nAChRs. It will be argued that the available evidence supports the conclusion that direct allosteric activation by allosteric agonists/ago-PAMs occurs via the same inter-subunit transmembrane site that has been identified for several α7-selective PAMs.

Type: Article
Title: Potentiation and allosteric agonist activation of α7 nicotinic acetylcholine receptors: binding sites and hypotheses
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.phrs.2023.106759
Publisher version: https://doi.org/10.1016/j.phrs.2023.106759
Language: English
Additional information: © 2023 The Authors. Published by Elsevier Ltd. under a Creative Commons license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Acetylcholine receptor, Allosteric agonist, Allosteric modulation, Binding site, Nicotinic acetylcholine receptor, Positive allosteric modulator
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10168304
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