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TRPC4/5 inhibitors: Phase I results and proof of concept studies
Simone Grimm1,2, Stefan Just3, Rene Fuertig3
1Medical School Berlin, Rüdesheimer Str., 5014197, Berlin, Germany. simone.grimm@medicalschool-berlin.de.
Abstract:
Transient receptor potential canonical (TRPC) ion channels are expressed in areas of the brain responsible for processing emotion and mood and have been implicated in the pathophysiology of internalizing disorders such as major depressive disorder and anxiety disorders. This review outlines the rationale for targeting TRPC ion channels for drug development, with specific focus on TRPC4 and TRPC5. We provide preclinical evidence that the lack of TRPC4 and TRPC5 channels or its pharmacological inhibition attenuate fear and anxiety without impairing other behaviors in mice. We also report on clinical studies of BI 1358894, a small molecule inhibitor of TRPC4/5 ion channels, demonstrating reduced psychological and physiological responses to induced anxiety/panic-like symptoms in healthy volunteers. Furthermore, we highlight an imaging study that investigated the acute effects of BI 1358894 and showed reduced activation in several brain regions involved in emotional processing. We conclude that these findings demonstrate a critical role for TRPC4 and TRPC5 in emotional processing, even though it remains an open question if the biological signatures of TRPC4/5 inhibition reported here translate into clinical efficacy and indicate that a TRPC4/5 inhibitor might provide a more effective treatment of internalizing disorders.
Insights
Targeting Transient Receptor Potential Canonical (TRPC) ion channels, specifically TRPC4 and TRPC5, shows promise for treating internalizing disorders. Inhibiting these channels reduced anxiety-like behaviors and symptoms in preclinical and clinical studies.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Transient Receptor Potential Canonical (TRPC) ion channels are implicated in the pathophysiology of internalizing disorders like depression and anxiety.
- TRPC channels are expressed in brain regions crucial for emotional processing.
Purpose of the Study:
- To review the rationale for targeting TRPC ion channels, particularly TRPC4 and TRPC5, for drug development.
- To present preclinical and clinical evidence supporting TRPC4/5 inhibition for internalizing disorders.
Main Methods:
- Preclinical studies in mice involving TRPC4/5 channel knockout or pharmacological inhibition.
- Clinical studies with BI 1358894, a TRPC4/5 inhibitor, in healthy volunteers.
- Neuroimaging studies to assess the acute effects of BI 1358894 on brain activity.
Main Results:
- TRPC4 and TRPC5 deficiency or inhibition attenuated fear and anxiety behaviors in mice without affecting other behaviors.
- BI 1358894 reduced psychological and physiological responses to induced anxiety/panic-like symptoms in humans.
- Neuroimaging revealed reduced activation in emotion-processing brain regions following BI 1358894 administration.
Conclusions:
- TRPC4 and TRPC5 play a critical role in emotional processing.
- TRPC4/5 inhibition demonstrates potential as a therapeutic strategy for internalizing disorders.
- Further research is needed to confirm clinical efficacy for treating major depressive disorder and anxiety disorders.
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