The α7 nicotinic acetylcholine receptor ligands methyllycaconitine, NS6740 and GTS-21 reduce lipopolysaccharide-induced TNF-α release from microglia

Thomsen, Morgane; Mikkelsen, Jens D.

doi:10.1016/j.jneuroim.2012.07.006

Cited by 115 publications

(106 citation statements)

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“…Although there have been some doubts concerning targeting a7 nAChRs in the treatment of colitis [e.g., it has been suggested that a7 nAChRs agonists worsen the disease (Snoek et al, 2010)], we suggest that alteration of the frequencies of FoxP3 1 -and/or IL-17A 1 -expressing T cells may underlie the beneficial effects of encenicline on intestinal inflammation. Furthermore we highlight the superiority of partial over full a7 nAChR agonists in the treatment of colitis, which is supported by recent reports showing on one hand that in vitro partial a7 nAChR agonists exhibit anti-inflammatory properties (Thomsen and Mikkelsen, 2012) and on the other indicating that full agonists do not affect colitis in vivo (Snoek et al, 2010).…”

Section: Encenicline In Colitissupporting

confidence: 83%

Encenicline, an 7 Nicotinic Acetylcholine Receptor Partial Agonist, Reduces Immune Cell Infiltration in the Colon and Improves Experimental Colitis in Mice

Sałaga

Blomster

Piechota-Polańczyk³

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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The a7 pentamer nicotinic acetylcholine receptors (nAChRs) are a target in transduction of anti-inflammatory signals from the central nervous system to the gastrointestinal (GI) tract. The aim of this study was to investigate the anti-inflammatory action of the novel a7 nAChR partial agonist encenicline and to determine the mechanism underlying its activity. Anti-inflammatory activity of encenicline was evaluated using trinitrobenzenesulfonic acid (TNBS)-and dextran sulfate sodium (DSS)-induced models of colitis. Macroscopic score, ulcer score, colon length and thickness, as well as myeloperoxidase (MPO) activity were recorded. Immunohistochemistry (IHC) was used to measure the infiltration of immune cells in the colon. Furthermore, we employed flow cytometry to determine the effect of encenicline on frequencies of FoxP3 1 and interleukin (IL)-17A 1 T cells in the mouse colon. Encenicline attenuated TNBS-and DSS-induced colitis in mice via a7 nAChRs, as indicated by significantly reduced macroscopic parameters and MPO activity. Treatment with encenicline significantly reduced the infiltration of macrophages, neutrophils, and B cells in the colon of TNBS-treated animals, as indicated by IHC. In the TNBS model encenicline reduced the frequency of FoxP3

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Section: Encenicline In Colitissupporting

confidence: 83%

Encenicline, an 7 Nicotinic Acetylcholine Receptor Partial Agonist, Reduces Immune Cell Infiltration in the Colon and Improves Experimental Colitis in Mice

Sałaga

Blomster

Piechota-Polańczyk³

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…This discovery provided a compelling motivation to reconsider our view of a 7 and other nAChRs strictly as mediators of transmembrane signals relying on channel-mediated ion flux. The non-neuronal cells that mediate a 7 's control of inflammation have not been shown to generate a 7 -mediated currents; moreover, some a 7 -targeting ligands that can effectively control inflammation have little or no efficacy as ion channel activators (van Maanen et al, 2009;Thomsen and Mikkelsen, 2012;Clark et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…One of the first such compounds to be identified was NS-6740 (Thomsen and Mikkelsen, 2012), and we have also characterized the compounds KC-1 (59-phenyl-3,4,5,6-tetrahydro-2,39-bipyridine) (Chojnacka et al, 2013), R-47 [(R)-N-(4-methoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide] (Clark et al, 2014), also known as CTI-15072 (van Maanen et al, 2009), as silent agonists. These compounds are large and structurally diverse, so here we start with the smallest a 7 agonists to find the most rudimentary structure capable of silent agonism, which is that of TEA.…”

Section: Discussionmentioning

confidence: 99%

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The Minimal Pharmacophore for Silent Agonism of the α₇ Nicotinic Acetylcholine Receptor

Papke

Chojnacka

Horenstein

2014

J Pharmacol Exp Ther

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The minimum pharmacophore for activation of the human a 7 nicotinic acetylcholine receptor (nAChR) is the tetramethylammonium cation. Previous work demonstrated that larger quaternary ammonium compounds, such as diethyldimethylammonium or 1-methyl quinuclidine, were a 7 -selective partial agonists, but additional increase in the size of the ammonium cation or the quinuclidine N-alkyl group by a single carbon to an N-ethyl group led to a loss of efficacy for ion channel activation. We report that although such compounds are ineffective at inducing the normal channel open state, they nonetheless regulate the induction of specific conformational states normally considered downstream of channel activation. We synthesized several panels of quaternary ammonium nAChR ligands that systematically varied the size of the substituents bonded to the central positively charged nitrogen atom. In these molecular series, we found a correlation between the molecular volume of the ligand and/or charge density, and the receptor's preferred distribution among conformational states including the closed state, the active state, a nonconducting state that could be converted to an activated state by a positive allosteric modulator (PAM), and a PAM-insensitive nonconducting state. We hypothesize that the changes of molecular volume of an agonist's cationic core subtly impact interactions at the subunit interface constituting the orthosteric binding site in such a way as to regulate the probability of conversions among the conformational states. We define a new minimal pharmacophore for the class of compounds we have termed "silent agonists," which are able to induce allosteric modulator-dependent activation but not the normal activated state.

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“…Of course, even a partial agonist with low channel activation efficacy may still be quite effective at inducing structural changes associated with the desensitized conformations of the receptor (44), and this has led to the hypothesis that ␣7 function, especially in non-neuronal cells incapable of ion-channel signaling, may be due to the ability of orthosteric ligands to induce global changes in receptor structure that can be transmitted to the receptor's protein interactome (45,46) and accomplish metabotropic type signaling (47-49). The potential importance for signaling through non-conducting states is also supported by the identification of silent agonists (50) such as NS6740 (51,52), which has been shown to be a very effective analgesic in several models of inflammatory or neuropathic pain (53), although its primary effect on channel activity is desensitization.…”

Section: Discussionmentioning

confidence: 99%

Critical Molecular Determinants of α7 Nicotinic Acetylcholine Receptor Allosteric Activation

Horenstein

Papke

Kulkarni

et al. 2016

Journal of Biological Chemistry

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The ␣7 nicotinic acetylcholine receptors (nAChRs) are uniquely sensitive to selective positive allosteric modulators (PAMs), which increase the efficiency of channel activation to a level greater than that of other nAChRs. Although PAMs must work in concert with "orthosteric" agonists, compounds such as GAT107 ((3aR,4S,9bS)-4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) have the combined properties of agonists and PAMs (ago-PAM) and produce very effective channel activation (direct allosteric activation (DAA)) by operating at two distinct sites in the absence of added agonist. One site is likely to be the same transmembrane site where PAMs like PNU-120596 function. We show that the other site, required for direct activation, is likely to be solventaccessible at the extracellular domain vestibule. We identify key attributes of molecules in this family that are able to act at the DAA site through variation at the aryl ring substituent of the tetrahydroquinoline ring system and with two different classes of competitive antagonists of DAA. Analyses of molecular features of effective allosteric agonists allow us to propose a binding model for the DAA site, featuring a largely non-polar pocket accessed from the extracellular vestibule with an important role for Asp-101. This hypothesis is supported with data from sitedirected mutants. Future refinement of the model and the characterization of specific GAT107 analogs will allow us to define critical structural elements that can be mapped onto the receptor surface for an improved understanding of this novel way to target ␣7 nAChR therapeutically.The ␣7 nicotinic acetylcholine receptor (nAChR) 3 is a recognized target for both central nervous system disorders, such as Alzheimer disease and schizophrenia, and peripheral indications, such as inflammation and associated pain (1, 2). As with other nicotinic receptors, conventional thinking has focused on the function of ␣7 as a ligand-gated ion channel that is activated by the transmitter acetylcholine (ACh). However, this traditional perspective has been challenged and enlarged upon by numerous observations. First, ␣7 receptors can be activated by choline as well as ACh (3), removing it from the position of being strictly optimized for synaptic function and suggesting that it may respond to tissue factors, especially in the context of playing a role in the modulation of inflammation (4). Additional insights have come from the exploration of the rich pharmacology of this receptor, beginning with the identification of a variety of selective agonists and partial agonists that control the conformational dynamics of activation and desensitization in ways that are totally unlike the behavior of other nAChRs, such as those of the neuromuscular junction and autonomic ganglia that are clearly optimized for fast synaptic transmission (1, 5). To a large degree, the specializations of synaptic nAChR arise from the evolution of different types of subunits that create the ACh-binding site at the interfa...

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The α7 nicotinic acetylcholine receptor ligands methyllycaconitine, NS6740 and GTS-21 reduce lipopolysaccharide-induced TNF-α release from microglia

Cited by 115 publications

References 52 publications

Encenicline, an 7 Nicotinic Acetylcholine Receptor Partial Agonist, Reduces Immune Cell Infiltration in the Colon and Improves Experimental Colitis in Mice

Encenicline, an 7 Nicotinic Acetylcholine Receptor Partial Agonist, Reduces Immune Cell Infiltration in the Colon and Improves Experimental Colitis in Mice

The Minimal Pharmacophore for Silent Agonism of the α₇ Nicotinic Acetylcholine Receptor

Critical Molecular Determinants of α7 Nicotinic Acetylcholine Receptor Allosteric Activation

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The α7 nicotinic acetylcholine receptor ligands methyllycaconitine, NS6740 and GTS-21 reduce lipopolysaccharide-induced TNF-α release from microglia

Cited by 115 publications

References 52 publications

Encenicline, an 7 Nicotinic Acetylcholine Receptor Partial Agonist, Reduces Immune Cell Infiltration in the Colon and Improves Experimental Colitis in Mice

Encenicline, an 7 Nicotinic Acetylcholine Receptor Partial Agonist, Reduces Immune Cell Infiltration in the Colon and Improves Experimental Colitis in Mice

The Minimal Pharmacophore for Silent Agonism of the α7 Nicotinic Acetylcholine Receptor

Critical Molecular Determinants of α7 Nicotinic Acetylcholine Receptor Allosteric Activation

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The Minimal Pharmacophore for Silent Agonism of the α₇ Nicotinic Acetylcholine Receptor