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

ABSTRACT: 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 (K₅₀ 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 (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.

SUBMITTER: Brimson JM 

PROVIDER: S-EPMC7280195 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature