Simple ammonium salts acting on sigma-1 receptors yield potential treatments for cancer and depression.
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Authors
Abbas, Haider
Issue Date
2020-06-08
Journal
Type
Article
Peer-Reviewed Publication
Peer-Reviewed Publication
Keywords
Ammonium salts
Ammonium compounds
Antidepressive agents
Antineoplastic agents
Calcium
Cancer
Cell proliferation
Cell proliferation
Dementia
Chemotherapy
Depression
MCF-7 cells
Molecular targeted therapy
Neoplasms
Pharmacy services
Receptor Pharmacology
Sigma receptors
Treatment
Ammonium compounds
Antidepressive agents
Antineoplastic agents
Calcium
Cancer
Cell proliferation
Cell proliferation
Dementia
Chemotherapy
Depression
MCF-7 cells
Molecular targeted therapy
Neoplasms
Pharmacy services
Receptor Pharmacology
Sigma receptors
Treatment
Journal Title
Scientific Reports
Volume
10
Issue
1
Begin page
9251
End page
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 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.
Citation
Brimson 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. Sci Rep. 2020 Jun 8;10(1):9251. doi: 10.1038/s41598-020-65849-6. PMID: 32514120; PMCID: PMC7280195.