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Antidepressant-like activity of a brain penetrant HCN channel inhibitor in mice
Changes in Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) channel function have been linked to depressive-like traits, making them potential drug targets. However, there is currently no peer-reviewed data supporting the use of a small molecule modulator of HCN channels in depression treat...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10206048/ https://www.ncbi.nlm.nih.gov/pubmed/37234718 http://dx.doi.org/10.3389/fphar.2023.1159527 |
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author | Pinares-Garcia, Paulo Spyrou, James McKenzie, Chaseley E. Forster, Ian C. Soh, Ming S. Mohamed Syazwan, Erlina Atif, Mohammed Reid, Christopher A. |
author_facet | Pinares-Garcia, Paulo Spyrou, James McKenzie, Chaseley E. Forster, Ian C. Soh, Ming S. Mohamed Syazwan, Erlina Atif, Mohammed Reid, Christopher A. |
author_sort | Pinares-Garcia, Paulo |
collection | PubMed |
description | Changes in Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) channel function have been linked to depressive-like traits, making them potential drug targets. However, there is currently no peer-reviewed data supporting the use of a small molecule modulator of HCN channels in depression treatment. Org 34167, a benzisoxazole derivative, has been patented for the treatment of depression and progressed to Phase I trials. In the current study, we analysed the biophysical effects of Org 34167 on HCN channels in stably transfected human embryonic kidney 293 (HEK293) cells and mouse layer V neurons using patch-clamp electrophysiology, and we utilised three high-throughput screens for depressive-like behaviour to assess the activity of Org 34167 in mice. The impact of Org 34167 on locomotion and coordination were measured by performing rotarod and ledged beam tests. Org 34167 is a broad-spectrum inhibitor of HCN channels, slowing activation and causing a hyperpolarising shift in voltage-dependence of activation. It also reduced I (h)-mediated sag in mouse neurons. Org 34167 (0.5 mg/kg) reduced marble burying and increased the time spent mobile in the Porsolt swim and tail suspension tests in both male and female BALB/c mice, suggesting reduced depressive-like behaviour. Although no adverse effects were seen at 0.5 mg/kg, an increase in dose to 1 mg/kg resulted in visible tremors and impaired locomotion and coordination. These data support the premise that HCN channels are valid targets for anti-depressive drugs albeit with a narrow therapeutic index. Drugs with higher HCN subtype selectivity are needed to establish if a wider therapeutic window can be obtained. |
format | Online Article Text |
id | pubmed-10206048 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-102060482023-05-25 Antidepressant-like activity of a brain penetrant HCN channel inhibitor in mice Pinares-Garcia, Paulo Spyrou, James McKenzie, Chaseley E. Forster, Ian C. Soh, Ming S. Mohamed Syazwan, Erlina Atif, Mohammed Reid, Christopher A. Front Pharmacol Pharmacology Changes in Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) channel function have been linked to depressive-like traits, making them potential drug targets. However, there is currently no peer-reviewed data supporting the use of a small molecule modulator of HCN channels in depression treatment. Org 34167, a benzisoxazole derivative, has been patented for the treatment of depression and progressed to Phase I trials. In the current study, we analysed the biophysical effects of Org 34167 on HCN channels in stably transfected human embryonic kidney 293 (HEK293) cells and mouse layer V neurons using patch-clamp electrophysiology, and we utilised three high-throughput screens for depressive-like behaviour to assess the activity of Org 34167 in mice. The impact of Org 34167 on locomotion and coordination were measured by performing rotarod and ledged beam tests. Org 34167 is a broad-spectrum inhibitor of HCN channels, slowing activation and causing a hyperpolarising shift in voltage-dependence of activation. It also reduced I (h)-mediated sag in mouse neurons. Org 34167 (0.5 mg/kg) reduced marble burying and increased the time spent mobile in the Porsolt swim and tail suspension tests in both male and female BALB/c mice, suggesting reduced depressive-like behaviour. Although no adverse effects were seen at 0.5 mg/kg, an increase in dose to 1 mg/kg resulted in visible tremors and impaired locomotion and coordination. These data support the premise that HCN channels are valid targets for anti-depressive drugs albeit with a narrow therapeutic index. Drugs with higher HCN subtype selectivity are needed to establish if a wider therapeutic window can be obtained. Frontiers Media S.A. 2023-05-10 /pmc/articles/PMC10206048/ /pubmed/37234718 http://dx.doi.org/10.3389/fphar.2023.1159527 Text en Copyright © 2023 Pinares-Garcia, Spyrou, McKenzie, Forster, Soh, Mohamed Syazwan, Atif and Reid. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Pinares-Garcia, Paulo Spyrou, James McKenzie, Chaseley E. Forster, Ian C. Soh, Ming S. Mohamed Syazwan, Erlina Atif, Mohammed Reid, Christopher A. Antidepressant-like activity of a brain penetrant HCN channel inhibitor in mice |
title | Antidepressant-like activity of a brain penetrant HCN channel inhibitor in mice |
title_full | Antidepressant-like activity of a brain penetrant HCN channel inhibitor in mice |
title_fullStr | Antidepressant-like activity of a brain penetrant HCN channel inhibitor in mice |
title_full_unstemmed | Antidepressant-like activity of a brain penetrant HCN channel inhibitor in mice |
title_short | Antidepressant-like activity of a brain penetrant HCN channel inhibitor in mice |
title_sort | antidepressant-like activity of a brain penetrant hcn channel inhibitor in mice |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10206048/ https://www.ncbi.nlm.nih.gov/pubmed/37234718 http://dx.doi.org/10.3389/fphar.2023.1159527 |
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