title: Structurally similar allosteric modulators of α7 nicotinic acetylcholine receptors exhibit five distinct pharmacological effects.
abstract: Activation of nicotinic acetylcholine receptors (nAChRs) is associated with the binding of agonists such as acetylcholine to an extracellular site that is located at the interface between two adjacent receptor subunits. More recently, there has been considerable interest in compounds, such as positive and negative allosteric modulators (PAMs and NAMs), that are able to modulate nAChR function by binding to distinct allosteric sites. Here we examined a series of compounds differing only in methyl substitution of a single aromatic ring. This series of compounds includes a previously described α7-selective allosteric agonist, cis-cis-4-p-tolyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide (4MP-TQS), together with all other possible combinations of methyl substitution at a phenyl ring (18 additional compounds). Studies conducted with this series of compounds have revealed five distinct pharmacological effects on α7 nAChRs. These five effects can be summarized as: 1) nondesensitizing activation (allosteric agonists), 2) potentiation associated with minimal effects on receptor desensitization (type I PAMs), 3) potentiation associated with reduced desensitization (type II PAMs), 4) noncompetitive antagonism (NAMs), and 5) compounds that have no effect on orthosteric agonist responses but block allosteric modulation (silent allosteric modulators (SAMs)). Several lines of experimental evidence are consistent with all of these compounds acting at a common, transmembrane allosteric site. Notably, all of these chemically similar compounds that have been classified as nondesensitizing allosteric agonists or as nondesensitizing (type II) PAMs are cis-cis-diastereoisomers, whereas all of the NAMs, SAMs, and type I PAMs are cis-trans-diastereoisomers. Our data illustrate the remarkable pharmacological diversity of allosteric modulators acting on nAChRs.
authors.affiliation: From the Department of Neuroscience, Physiology & Pharmacology, University College London, London, WC1E 6BT, United Kingdom and.
authors.forename: JasKiran K
authors.initials: JK
authors.lastname: Gill-Thind
authors.affiliation: the Department of Chemistry, University College London, London, WC1H 0AJ, United Kingdom.
authors.forename: Persis
authors.initials: P
authors.lastname: Dhankher
authors.affiliation: the Department of Chemistry, University College London, London, WC1H 0AJ, United Kingdom.
authors.forename: Jarryl M
authors.initials: JM
authors.lastname: D'Oyley
authors.affiliation: the Department of Chemistry, University College London, London, WC1H 0AJ, United Kingdom.
authors.forename: Tom D
authors.initials: TD
authors.lastname: Sheppard
authors.affiliation: From the Department of Neuroscience, Physiology & Pharmacology, University College London, London, WC1E 6BT, United Kingdom and n.millar@ucl.ac.uk.
authors.forename: Neil S
authors.initials: NS
authors.lastname: Millar
mesh_terms: D000495:Allosteric Site; D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D018722:Nicotinic Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology*; D014981:Xenopus; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: C000597476:4-p-tolyl-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinoline-8-sulfonamide; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011804:Quinolines; D013449:Sulfonamides; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: Cys Loop Receptor; Membrane Protein; Molecular Pharmacology; Neurobiology; Nicotinic Acetylcholine Receptors (nAChR); Receptor Structure-Function