Insights Into the Differential Desensitization of<i>α</i>4<i>β</i>2 Nicotinic Acetylcholine Receptor Isoforms Obtained With Positive Allosteric Modulation of Mutant Receptors

Papke, Roger L.; Stokes, Clare

doi:10.1124/molpharm.122.000591

Cited by 3 publications

(2 citation statements)

References 94 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In recent years, the discovery of nAChR expression in cells of the immune system has led to an additional perspective on nAChR function, since in these cells the proteins do not appear to form functional ion channels but rather subserve metabotropic functions more commonly associated with G protein-coupled receptors. , A functional role for these receptors in regulating inflammation and pain was first described as a cholinergic anti-inflammatory pathway that involved activation by the vagus nerve, − but may also be independent of vagus nerve activation, constituting more generally a cholinergic anti-inflammatory system (CAS). − Early studies of CAS focused on α7 nAChR and selective ligands, such as GTS-21. , However, GTS-21 is only a partial agonist of α7 and additionally strongly desensitizing of both α7 and other nAChR . As noted above, the nAChR of immune cells are, in a sense, noncanonical since they do not generate ion-channel currents, and numerous ligands that are effective modulators of CAS have been identified, not based on their ability to activate currents, but for their effectiveness at inducing nonconducting states normally associated with desensitization.…”

Section: Introductionmentioning

confidence: 99%

“…17,18 However, GTS-21 is only a partial agonist of α7 and additionally strongly desensitizing of both α7 19 and other nAChR. 20 As noted above, the nAChR of immune cells are, in a sense, noncanonical since they do not generate ion-channel currents, and numerous ligands that are effective modulators of CAS have been identified, not based on their ability to activate currents, but for their effectiveness at inducing nonconducting states normally associated with desensitization. One such class of ligands has been referred to as "silent agonists".…”

Section: ■ Introductionmentioning

confidence: 99%

See 1 more Smart Citation

New Alpha9 nAChR Ligands Based on a 5-(Quinuclidin-3-ylmethyl)-1,2,4-oxadiazole Scaffold

Dallanoce,

Richter,

Stokes

et al. 2024

ACS Chem. Neurosci.

Self Cite

View full text Add to dashboard Cite

Several lines of evidence have indicated that nicotinic acetylcholine receptors (nAChR) that contain α9 subunits, probably in combination with α10 subunits, may be valuable targets for the management of pain associated with inflammatory diseases through a cholinergic antiinflammatory system (CAS), which has also been associated with α7 nAChR. Both α7and α9-containing neuronal nAChR can be pharmacologically distinguished from the high-affinity nicotinic receptors of the brain by their sensitivity to α-bungarotoxin, but in other ways, they have quite distinct pharmacological profiles. The early association of α7 with CAS led to the development of numerous new ligands, variously characterized as α7 agonists, partial agonists, or silent agonists that desensitized α7 receptors without activation. Subsequent reinvestigation of one such family of α7 ligands based on an N,N-diethyl-N′-phenylpiperazine scaffold led to the identification of potent agonists and antagonists for α9. In this paper, we characterize the α9/α10 activity of a series of compounds based on a 5-(quinuclidin-3-ylmethyl)-1,2,4-oxadiazole (QMO) scaffold and identify two new potent ligands of α9, QMO-28, an agonist, and QMO-17, an antagonist. We separated the stereoisomers of these compounds to identify the most potent agonist and discovered that only the 3R isomer of QMO-17 was an α9 antagonist, permitting an in silico model of α9 antagonism to be developed. The α9 activity of these compounds was confirmed to be potentially useful for CAS management of inflammatory pain in cell-based assays of cytokine release.

show abstract