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

Scientific Reports
J M BrimsonStephen T Safrany

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 (Ki 43 nM), tripentylammonium (Ki 15 nM) and trihexylammonium (Ki 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 (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 t...Continue Reading

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Citations

Aug 5, 2020·Expert Opinion on Therapeutic Targets·James Michael BrimsonTewin Tencomnao
Oct 1, 2020·International Journal of Molecular Sciences·Mikhail V VoroninSergei B Seredenin
May 1, 2021·International Journal of Molecular Sciences·Vladimir ZhemkovIlya Bezprozvanny

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Methods Mentioned

BETA
saturation binding
Assay
PCR
transfection

Software Mentioned

Softmax Pro
GraphPad Prism

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