Antidepressant-like activity of a brain penetrant HCN channel inhibitor in mice

Frontiers in Pharmacology

Pharmacology

Chaseley E. McKenzie¹  Mohammed Atif¹  Paulo Pinares-Garcia¹  Ian C. Forster¹  Ming S. Soh¹  James Spyrou¹  Erlina Mohamed Syazwan¹  Christopher A. Reid² 

[1] Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia;Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia;Epilepsy Research Centre, Department of Medicine, University of Melbourne, Heidelberg, VIC, Australia;

关键词: HCN channels;    small molecule;    antidepressant;    depression;    mood disorder;    HCN channel block;   

DOI  :  10.3389/fphar.2023.1159527

 received in 2023-02-06, accepted in 2023-04-27,  发布年份 2023

来源: Frontiers

【 摘 要 】

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 Ih-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.

【 授权许可】

Unknown   
Copyright © 2023 Pinares-Garcia, Spyrou, McKenzie, Forster, Soh, Mohamed Syazwan, Atif and Reid.