Sulfonium as a Surrogate for Ammonium: A New α7 Nicotinic Acetylcholine Receptor Partial Agonist with Desensitizing Activity

Quadri, Marta; Stokes, Clare; Gulsevin, Alican; Felts, Ashley C.; Abboud, Khalil A.; Papke, Roger L.; Horenstein, Nicole A.

doi:10.1021/acs.jmedchem.7b00875

Cited by 12 publications

(13 citation statements)

References 28 publications

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“…The diEPP family of a7 ligands were originally designed based on the nonselective orthosteric ganglionic nAChR agonist dimethylphenylpiperazinium, and they have been shown to act as a7 antagonists, partial agonists, and silent agonists depending on the substitution of the phenyl ring or the nature of the charged group (Quadri et al, 2016(Quadri et al, , 2017Horenstein and Papke, 2017). In the present work, we identified the allosteric agonism of a diEPP derivative, 2NDEP, formerly reported as a weak partial agonist of a7 nAChR.…”

Section: Discussionmentioning

confidence: 85%

Allosteric Agonism of α7 Nicotinic Acetylcholine Receptors: Receptor Modulation Outside the Orthosteric Site

et al. 2019

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Nicotinic acetylcholine receptors (nAChRs) are members of the Cys-loop superfamily of ligand-gated ion channels. Typically, channel activation follows the binding of agonists to the orthosteric binding sites of the receptor. a7 nAChRs have a very low probability of channel activation, which can be reversed by the binding of a7 selective positive allosteric modulators (PAMs) to putative sites within the transmembrane domains. Although typical PAMs, like PNU-120596, require coapplication of an orthosteric agonist to produce large channel activations, some, like GAT107 and B-973B [(S)-3-(3,4-difluorophenyl)-N-(1-(6-(4-(pyridin-2-yl)piperazin-1-yl)pyrazin-2-yl)ethyl)propanamide], are characterized as allosteric activating PAMs, which also bind to an allosteric activation (AA) site in the extracellular domain and activate the a7 ion channel by themselves. We had previously characterized N,N-diethyl-N9-phenylpiperazine analogs with various functions. In this work, we docked members of this family to a homology model of the a7 receptor extracellular domain. The compound 1,1-diethyl-4(naphthalene-2-yl)piperazin-1-ium (2NDEP) a weak partial agonist, showed particularly favorable docking and binding energies at the putative AA site of the receptor. We hypothesized that 2NDEP could couple with PAMs through the AA site. This hypothesis was tested with the a7 mutant C190A, which is not activated by orthosteric agonists but is effectively activated by GAT107. The results showed that 2NDEP acts as an allosteric agonist of a7C190A when coapplied with the PAM PNU-120596. Also, the allosteric activity was nearly abolished upon coapplication with the AA site-selective antagonist 2,3,5,6MP-TQS (cis-trans-4-(2,3,5,6-tetramethylphenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide), consistent with AA site involvement. Overall, our findings show a novel mode of agonism through an allosteric site in the extracellular domain of a7 nAChR.

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Section: Discussionmentioning

confidence: 85%

Allosteric Agonism of α7 Nicotinic Acetylcholine Receptors: Receptor Modulation Outside the Orthosteric Site

et al. 2019

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“…Different silent compounds (Fig. 1B) such as NS-6740 ( 14 ) [38], KC-1 ( 15 ) [36], ASM-024 ( 16 ) [39], diEPP ( 17 ) [40], p -CF 3 -diEPP ( 18 ) [41], the sulfonium salt 19 [42], and the spirocyclic quinuclidine derivatives 20a and 20b [43] were identified, and some of them proved to be effective in in vivo anti-inflammatory chronic pain models [44,45]. The study of ligands selective for the α7 receptor evidenced the presence of common pharmacophoric elements in the structures of most full-partial [20,21,25,46–49] as well as silent agonists [36,38–43], including a basic amine, a central group with hydrogen-bond acceptor properties and a lipophilic aryl moiety extending from the amine (Fig.…”

Section: Introductionmentioning

confidence: 99%

Novel 5-(quinuclidin-3-ylmethyl)-1,2,4-oxadiazoles to investigate the activation of the α7 nicotinic acetylcholine receptor subtype: Synthesis and electrophysiological evaluation

Quadri

Silnović

Matera

et al. 2018

European Journal of Medicinal Chemistry

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α7 nicotinic acetylcholine receptors (nAChRs) are relevant therapeutic targets for a variety of disorders including neurodegeneration, cognitive impairment, and inflammation. Although traditionally identified as an ionotropic receptor, the α7 subtype showed metabotropic-like functions, mainly linked to the modulation of immune responses. In the present work, we investigated the structure-activity relationships in a set of novel α7 ligands incorporating the 5-(quinuclidin-3-ylmethyl)-1,2,4-oxadiazole scaffold, i.e. derivatives 21a-34a and 21b-34b, aiming to identify the structural requirements able to preferentially trigger one of the two activation modes of this receptor subtype. The new compounds were characterized as partial and silent α7 nAChR agonists in electrophysiological assays, which allowed to assess the contribution of the different groups towards the final pharmacological profile. Overall, modifications of the selected structural backbone mainly afforded partial agonists, among them tertiary bases 27a-33a, whereas additional hydrogen-bond acceptor groups in permanently charged ligands, such as 29b and 31b, favored a silent desensitizing profile at the α7 nAChR.

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“…Since we had previously observed that the sulfonium compound, 1-ethyl-4-phenylthiomorpholin-1-ium trifluoromethanesulfonate [ 12 ], an analog of the diEPP silent agonists [ 21 ], behaved as a silent agonist of α7, inactive when applied alone but active when co-applied with an α7 PAM, we tested the sulfonium compounds in co-application with the type II PAM, 4-naphthalene-1-yl-3a,4,5,9b-tetrahydro-3- H -cyclopenta[c]quinoline-8-sulfonic acid amide (TQS) [ 22 ]. Compounds were co-applied at a concentration of 100 µM with 30 µM racemic TQS ( Figure 3 A).…”

Section: Resultsmentioning

confidence: 99%

“…Two exemplar compounds termed as “silent agonists” for their tendency to desensitize α7 receptors with minimal channel activation are NS6740 and para-trifluoromethyl N , N -diethyl- N ′-phenylpiperazinium iodide ( p -CF 3 diEPP) compounds [ 11 ]. We recently reported synthesis and electrophysiological characterization of a new sulfonium analog of the diethyl- N ′-phenylpiperazinium scaffold,1-ethyl-4-phenylthiomorpholin-1-ium trifluoromethane sulfonate, in which the quaternary ammonium nitrogen atom is replaced with a sulfur [ 12 ]. This compound provides a charge isostere for the ammonium group, yet is not directly analogous given that in the diEPP compound the nitrogen bears two ethyl groups whereas the sulfonium analog has only one.…”

Section: Introductionmentioning

confidence: 99%

Sulfonium Ligands of the α7 nAChR

2021

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The α7 nicotinic acetylcholine receptor (nAChR) is an important target given its role in cognitive function as well as in the cholinergic anti-inflammatory pathway, where ligands that are effective at stabilizing desensitized states of the receptor are of particular interest. The typical structural element associated with a good desensitizer is the ammonium pharmacophore, but recent work has identified that a trivalent sulfur, in the positively charged sulfonium form, can substitute for the nitrogen in the ammonium pharmacophore. However, the breadth and scope of employing the sulfonium group is largely unexplored. In this work, we have surveyed a disparate group of sulfonium compounds for their functional activity with α7 as well as other nAChR subtypes. Amongst them, we found that there is a wide range of ability to induce α7 desensitization, with 4-hydroxyphenyldimethylsulfonium and suplatast sulfonium salts being the most desensitizing. The smallest sulfonium compound, trimethylsulfonium, was a partial agonist for α7 and other neuronal nAChR. Molecular docking into the α7 receptor extracellular domain revealed preferred poses in the orthosteric binding site for all but one compound, with typical cation–pi interactions as seen with traditional ammonium compounds. A number of the compounds tested may serve as useful platforms for further development of α7 desensitizing ability and for receptor subtype selectivity.

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Sulfonium as a Surrogate for Ammonium: A New α7 Nicotinic Acetylcholine Receptor Partial Agonist with Desensitizing Activity

Cited by 12 publications

References 28 publications

Allosteric Agonism of α7 Nicotinic Acetylcholine Receptors: Receptor Modulation Outside the Orthosteric Site

Allosteric Agonism of α7 Nicotinic Acetylcholine Receptors: Receptor Modulation Outside the Orthosteric Site

Novel 5-(quinuclidin-3-ylmethyl)-1,2,4-oxadiazoles to investigate the activation of the α7 nicotinic acetylcholine receptor subtype: Synthesis and electrophysiological evaluation

Sulfonium Ligands of the α7 nAChR

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