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

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

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. ssafrany@rcsi-mub.com.
  • 11 Department of Pharmacy, University of Wolverhampton, Wulfruna Street, Wolverhampton, WV1 1LY, UK. ssafrany@rcsi-mub.com.
  • 12 RCSI-Bahrain, PO Box 15503, Adliya, Kingdom of Bahrain. ssafrany@rcsi-mub.com.
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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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-100985
    99.84%, Sigma-1 Receptor Antagonist