Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/32970
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dc.contributor.authorPinares-Garcia, Paulo-
dc.contributor.authorSpyrou, James-
dc.contributor.authorMcKenzie, Chaseley E-
dc.contributor.authorForster, Ian C-
dc.contributor.authorSoh, Ming S-
dc.contributor.authorMohamed Syazwan, Erlina-
dc.contributor.authorAtif, Mohammed-
dc.contributor.authorReid, Christopher A-
dc.date2023-
dc.date.accessioned2023-06-07T02:37:15Z-
dc.date.available2023-06-07T02:37:15Z-
dc.date.issued2023-05-
dc.identifier.citationFrontiers in Pharmacology 2023en_US
dc.identifier.urihttps://ahro.austin.org.au/austinjspui/handle/1/32970-
dc.description.abstractChanges 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.en_US
dc.language.isoeng-
dc.subjectHCN channel blocken_US
dc.subjectHCN channelsen_US
dc.subjectantidepressanten_US
dc.subjectdepressionen_US
dc.subjectmood disorderen_US
dc.subjectsmall moleculeen_US
dc.titleAntidepressant-like activity of a brain penetrant HCN channel inhibitor in mice.en_US
dc.typeJournal Articleen_US
dc.identifier.journaltitleFrontiers in Pharmacologyen_US
dc.identifier.affiliationThe Florey Institute of Neuroscience and Mental Healthen_US
dc.identifier.affiliationEpilepsy Research Centreen_US
dc.identifier.doi10.3389/fphar.2023.1159527en_US
dc.type.contentTexten_US
dc.identifier.pubmedid37234718-
dc.description.volume14-
dc.description.startpage1159527-
item.languageiso639-1en-
item.fulltextNo Fulltext-
item.grantfulltextnone-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.cerifentitytypePublications-
item.openairetypeJournal Article-
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