Recent work has shown that compounds that are effective desensitizers of ionotropic activity of the human α7 nicotinic acetylcholine receptor (nAChR) can have potent anti-inflammatory activity. We term these α7 nAChR desensitizers as “silent agonists” if they are extremely weak (&lt;10%) partial agonists relative to acetylcholine. Typical silent agonists contain an ammonium pharmacophore and can be as simple as tetraethylammonium, or more complex scaffolds including N,N-diethyl N’-arylpiperazines (diEPPs). In the work described here, we asked the simple question as to whether the ammonium pharmacophore of a silent agonist could be replaced with a sulfonium group. While the positive charge of the molecule is preserved, the sulfur group potentially impacts charge distribution, size and ring shape of the compound. We describe the synthesis and purification of 1-ethyl-4-phenylthiomorpholin-1-ium trifluoromethane sulfonate. We investigated the sulfonium isostere of diEPP in two-electrode voltage clamp electrophysiology (TEVC) on Xenopus oocytes expressing α7 and α4β2 nAChRs. The CRC (concentration-response curve) data confirm the sulfonium group binding to the nAChR orthosteric agonist site together with promoting α7 nonconducting desensitized states. The new sulfonium derivative showed no significant α7 ion channel activation (30 μM: 0.02 ± 0.00, relative to ACh controls) and co-application of positive allosteric modulator PNU-120596 (30 μM compound + 10 μM PNU: 4.8 ± 0.78, relative to ACh controls) revealed the desensitizing ability of the sulfonium compound. The sulfonium replacement achieved a 4-fold PNU response enhancement compared to N,N-diethyl-N’-phenylpiperazine (30 μM + 10 μM PNU: 1.3 ± 0.3, relative to ACh controls). The molecular electrostatic potential (MEP) was evaluated and shows the sulfonium positive charge is more distributed across the thiomorpholine ring, possibly allowing a better interaction with the π-cation box of the α7 receptor. These compounds may offer a therapeutic alternative relative to isosteric ammonium compounds via their lack of hydrogen bond donor functionality.

Synthesis and characterization of sulfonium silent agonists of the alpha 7 nicotinic receptor

255th National Meeting (2018)

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