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

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

doi:10.1038/s41598-020-65849-6

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

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

School of Biosciences

Research output: Contribution to journal › Article › peer-review

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 tailsuspension tests. Dipentylammonium (Ki 43 nM),tripentylammonium (Ki 15 nM) and trihexylammonium (Ki 9 nM) showed high affinity for the sigma-1receptor. 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.

Original language	English
Article number	9251
Journal	Scientific Reports
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41598-020-65849-6
Publication status	Published - 8 Jun 2020

Bibliographical note

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Access to Document

10.1038/s41598-020-65849-6

Simple ammonium salts acting on sigma-1 receptors
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Final published version, 1.48 MBLicence: CC BY 3.0

Cite this

@article{d4a4a738b01741b0a8faab89fc06663e,

title = "Simple ammonium salts acting on sigma-1 receptors yield potential treatments for cancer and depression",

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 tailsuspension tests. Dipentylammonium (Ki 43 nM),tripentylammonium (Ki 15 nM) and trihexylammonium (Ki 9 nM) showed high affinity for the sigma-1receptor. 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 ammoniumsalts act as sigma-1 receptor agonists and antagonists in vivo and require further investigation.",

author = "Brimson, {James M.} and Akula, {Kiran K.} and Haider Abbas and Ferry, {David R.} and Kulkarni, {Shrinivas K.} and Russell, {Steven T.} and Tisdale, {Michael J.} and Tewin Tencomnao and Safrany, {Stephen T.}",

note = "This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article{\textquoteright}s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.",

year = "2020",

month = jun,

day = "8",

doi = "10.1038/s41598-020-65849-6",

language = "English",

volume = "10",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Simple ammonium salts acting on sigma-1 receptors yield potential treatments for cancer and depression

AU - Brimson, James M.

AU - Akula, Kiran K.

AU - Abbas, Haider

AU - Ferry, David R.

AU - Kulkarni, Shrinivas K.

AU - Russell, Steven T.

AU - Tisdale, Michael J.

AU - Tencomnao, Tewin

AU - Safrany, Stephen T.

N1 - This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

PY - 2020/6/8

Y1 - 2020/6/8

N2 - 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 tailsuspension tests. Dipentylammonium (Ki 43 nM),tripentylammonium (Ki 15 nM) and trihexylammonium (Ki 9 nM) showed high affinity for the sigma-1receptor. 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 ammoniumsalts act as sigma-1 receptor agonists and antagonists in vivo and require further investigation.

AB - 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 tailsuspension tests. Dipentylammonium (Ki 43 nM),tripentylammonium (Ki 15 nM) and trihexylammonium (Ki 9 nM) showed high affinity for the sigma-1receptor. 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 ammoniumsalts act as sigma-1 receptor agonists and antagonists in vivo and require further investigation.

UR - http://www.nature.com/articles/s41598-020-65849-6

UR - http://www.scopus.com/inward/record.url?scp=85086157295&partnerID=8YFLogxK

U2 - 10.1038/s41598-020-65849-6

DO - 10.1038/s41598-020-65849-6

M3 - Article

SN - 2045-2322

VL - 10

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 9251

ER -

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

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Cite this