Abstract
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.
Highlights
Nicotinic acetylcholine receptors are a family of pentameric ligand-gated ion channels whose primary physiological agonist is acetylcholine (ACh) [1]
The sulfonium compounds (Figure 1) were evaluated for their ability to activate human α7 receptors expressed in Xenopus oocytes (Figure 2A)
The sulfonium compounds (Figure 1) were evaluated for their ability to man α7 receptors expressed in Xenopus oocytes (Figure 2A)
Summary
Nicotinic acetylcholine receptors (nAChR) are a family of pentameric ligand-gated ion channels whose primary physiological agonist is acetylcholine (ACh) [1]. Therephenylpiperazinium are a limitedscaffold,1-ethyl-4-phenylthiomorpholin-1-ium number of other examples of trifluoromethane using a sulfonium sulin which thecharged quaternarynitrogen, ammonium nitrogen atomgenerally, is replaced with a sulfur [12] This compound provides a charge isostere for the ammonium group, yet is not directly ter. Arecoline is angiven agonist fordiEPP muscarinic some receptors analogous that in the compound theand nitrogen bearsnicotinic two ethyl groups whereas [14]. For proteins with bound molecule ligandsto revealed that the sulfonium group, like the ammonium group, is a their chargesmall resemblance high-energy intermediates/transition states, for preferred chemotype for recognition inside protein aromatic binding cages [13].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
