Simple ammonium salts acting on sigma-1 receptors yield potential treatments for cancer and depression.
journal contributionposted on 25.01.2021, 09:38 by 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
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 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.
University of Bath, Dudley Group of Hospitals NHS Foundation Trust
The National Research University Project, Office of Higher Education Commission. NRU-59-057-AS.
Rachadapisek Sompote Fund for Postdoctoral Fellowship, Chulalongkorn University, Thailand.
CommentsThe original article is available at https://www.nature.com/
Published CitationBrimson JM, Akula KK, Abbas H, Ferry DR, Kulkarni SK, Russell ST, Tisdale MJ, Tencomnao T, Safrany ST. Simple ammonium salts acting on sigma-1 receptors yield potential treatments for cancer and depression. Scientific Reports. 2020;10(1):9251.
Publication Date8 June 2020
- RCSI Bahrain
PublisherNature Publishing Group
- Published Version (Version of Record)