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.
James M Brimson  1  2 ,  Kiran K Akula  3  4 ,  Haider Abbas  5  6  7 ,  David R Ferry  8 ,  Shrinivas K Kulkarni  3 ,  Steven T Russell  9 ,  Michael J Tisdale  9 ,  Tewin Tencomnao  1 ,  Stephen T Safrany  10  11  12
Affiliations
  • 1. Age-Related Inflammation and Degeneration Research Unit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, 10330, Thailand.
  • 2. Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
  • 3. University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India.
  • 4. Ultragenyx Pharmaceuticals Inc, Novato, California, CA94949, USA.
  • 5. Department of Pharmacy, University of Wolverhampton, Wulfruna Street, Wolverhampton, WV1 1LY, UK.
  • 6. New Cross Hospital, Wolverhampton, WV10 0QP, UK.
  • 7. University Hospital Birmingham NHS Foundation Trust, Mindelsohn Way, Birmingham, B15 2TH, UK.
  • 8. Eli Lilly, 893 S Delaware Street, Indianapolis, IN, 46225, USA.
  • 9. School of Health and Life Sciences, Aston University, Birmingham, B4 7ET, UK.
  • 10. Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK. [email protected].
  • 11. Department of Pharmacy, University of Wolverhampton, Wulfruna Street, Wolverhampton, WV1 1LY, UK. [email protected].
  • 12. RCSI-Bahrain, PO Box 15503, Adliya, Kingdom of Bahrain. [email protected].
PMID: 32514120 DOI: 10.1038/s41598-020-65849-6
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.

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