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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 tail suspension tests. Dipentylammonium (K i  43 nM), tripentylammonium (K i  15 nM) and trihexylammonium (K i  9 nM) showed high affinity for the sigma-1 receptor. Dioctanoylammonium had the highest affinity (K 50  0.05 nM); this also showed the highest affinity for sigma-2 receptors (K i  13 nM). Dipentylammonium was found to have antidepressant activity  in vivo . Branched-chain ammonium salts showed lower affinity. Bis(2-ethylhexyl)ammonium (K 50  29 µM), triisopentylammonium (K 50  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.

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