Simple ammonium salts acting on sigma-1 receptors yield potential treatments for cancer and depression

James M. Brimson, Kiran K. Akula, Haider Abbas, David R. Ferry, Shrinivas K. Kulkarni, Steven T. Russell, Michael J. Tisdale, Tewin Tencomnao, Stephen T. Safrany

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Sigma-1 and sigma-2 receptors are emerging therapeutic targets. We have identified that simple ammonium salts bind to these receptors and are effective in vivo. Radioligand binding assays were used to obtain structure-activity relationships of these salts. MTS assays were performed to determine their effect on growth in MCF7 and MDA-MB-486 cells. Anticancer properties were tested in NMRI mice transplanted with a fragment of mouse adenocarcinoma (MAC13). Antidepressant activity was tested using the forced-swim test and tailsuspension tests. Dipentylammonium (Ki 43 nM),tripentylammonium (Ki 15 nM) and trihexylammonium (Ki 9 nM) showed high affinity for the sigma-1receptor. Dioctanoylammonium had the highest affinity (K50 0.05 nM); this also showed the highest affinity for sigma-2 receptors (Ki 13 nM). Dipentylammonium was found to have antidepressant activity in vivo. Branched-chain ammonium salts showed lower affinity. Bis(2-ethylhexyl)ammonium (K50 29 μM), triisopentylammonium (K50 196 μM) and dioctanoylammonium showed a low Hill slope,and fitted a 2-site binding model for the sigma-1 receptor. We propose this two-site binding can be used to biochemically define a sigma-1 receptor antagonist. Bis(2-ethylhexyl)ammonium and triisopentylammonium were able to inhibit the growth of tumours in vivo. Cheap, simple ammonium
salts act as sigma-1 receptor agonists and antagonists in vivo and require further investigation.
Original languageEnglish
Article number 9251
JournalScientific Reports
Issue number1
Publication statusPublished - 8 Jun 2020

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