Sulfonium Moieties as Ammonium Bioisosteres: Novel Ligands for the Alpha7 Nicotinic Acetylcholine Receptor

In the pressing quest of novel treatments for chronic
pain, α7
nAChR silent agonists show efficacy as anti-inflammatory modulators
and represent a promising strategy. Recent findings reveal that a
sulfonium ion can replace the quaternary ammonium nitrogen as an alternative
pharmacophore for nAChR silent activation. This study reports the
design, synthesis, and electrophysiological evaluation of a new series
of sulfonium-based derivatives inspired by the archetypal silent agonist
NS6740. Our findings identify NSS-9 as a novel sulfonium
α7 silent agonist that effectively alleviates inflammatory pain
in a mouse model, highlighting it as a lead compound for further optimization.
These results provide insights into the potential of the sulfonium
group as a chemotype interacting with the α7 binding site, making
it a valuable scaffold for novel α7 silent agonists. Additionally,
sulfonium compounds were tested on α9 nAChR, also involved in
the cholinergic anti-inflammatory system, identifying one partial
agonist and two antagonists.