Abstract
Small conductance calcium-activated potassium (SK) channels are, as their name indicates, transmembrane proteins with the ability to selectively
conduct potassium ions through the cell membrane upon increased intracellular calcium concentrations. These channels are expressed throughout the human body and participate in important biological processes and diseases, making them interesting novel therapeutic targets to treat conditions such as cancer, neurological disorders and cardiovascular diseases.
Currently, one of the most promising therapeutic application concerning SK channels is treatment of atrial fibrillation, the most common type of sustained arrhythmia. In recent years, many studies have shown that pharmacological inhibition of SK channels has antiarrhythmic properties in multiple experimental models and protects the heart against new episodes of atrial fibrillation. More importantly, this effect selectively targets the upper chambers of the heart, the atria, and does not interfere with the function of ventricles, the lower chambers, an event that could trigger dangerous adverse effects associated with non-chamber selective antiarrhythmic drugs. However, there are some important limitations, such as the distribution into the central nervous system, that hinder the use of currently available SK inhibitors as drugs for the treatment of atrial fibrillation, and only recently has the first SK channel inhibitor been tested in a human clinical trial. Therefore, it is important to continue identifying new SK inhibitors that can
overcome these limitations and characterize them pharmacologically to assess their potency and selectivity as well as their general drugability. Further, it is relevant to understand how they bind to SK channels and the mechanism behind their inhibitory effect, which has been part of the
objectives in the present work.
This dissertation presents an updated review of available SK inhibitors, their molecular pharmacology, and potential application as new antiarrhythmic agents to treat atrial fibrillation. The review is followed by three scientific articles published during my PhD studies and containing most of the conducted work, which focused on the identification and characterization
of new SK inhibitors as well as the assessment of antiarrhythmic properties of the most promising candidates. These efforts resulted in the profiling of two new molecules, AP14145 and BBP, which contribute to the expanding field of SK inhibitors and address some of the limitations regarding their application as novel antiarrhythmic drugs. The final part of the dissertation engages in a discussion of the results obtained during the thesis as well as other understudied and challenging issues concerning pharmacological SK channel inhibition and possible ways to undertake them.
conduct potassium ions through the cell membrane upon increased intracellular calcium concentrations. These channels are expressed throughout the human body and participate in important biological processes and diseases, making them interesting novel therapeutic targets to treat conditions such as cancer, neurological disorders and cardiovascular diseases.
Currently, one of the most promising therapeutic application concerning SK channels is treatment of atrial fibrillation, the most common type of sustained arrhythmia. In recent years, many studies have shown that pharmacological inhibition of SK channels has antiarrhythmic properties in multiple experimental models and protects the heart against new episodes of atrial fibrillation. More importantly, this effect selectively targets the upper chambers of the heart, the atria, and does not interfere with the function of ventricles, the lower chambers, an event that could trigger dangerous adverse effects associated with non-chamber selective antiarrhythmic drugs. However, there are some important limitations, such as the distribution into the central nervous system, that hinder the use of currently available SK inhibitors as drugs for the treatment of atrial fibrillation, and only recently has the first SK channel inhibitor been tested in a human clinical trial. Therefore, it is important to continue identifying new SK inhibitors that can
overcome these limitations and characterize them pharmacologically to assess their potency and selectivity as well as their general drugability. Further, it is relevant to understand how they bind to SK channels and the mechanism behind their inhibitory effect, which has been part of the
objectives in the present work.
This dissertation presents an updated review of available SK inhibitors, their molecular pharmacology, and potential application as new antiarrhythmic agents to treat atrial fibrillation. The review is followed by three scientific articles published during my PhD studies and containing most of the conducted work, which focused on the identification and characterization
of new SK inhibitors as well as the assessment of antiarrhythmic properties of the most promising candidates. These efforts resulted in the profiling of two new molecules, AP14145 and BBP, which contribute to the expanding field of SK inhibitors and address some of the limitations regarding their application as novel antiarrhythmic drugs. The final part of the dissertation engages in a discussion of the results obtained during the thesis as well as other understudied and challenging issues concerning pharmacological SK channel inhibition and possible ways to undertake them.
| Original language | English |
|---|
| Number of pages | 70 |
|---|---|
| Publication status | Published - 12 Feb 2019 |
| Event | PhD Defence, Rafel Simó Vicens: Pharmacological inhibition of SK channels, an atria-specific antiarrhythmic strategy - Henrik Dam Auditorium, Mærsk Tower, Blegdamsvej 3B, 2200 København N, Copenhagen, Denmark Duration: 25 Apr 2019 → 25 Apr 2019 |
Other
| Other | PhD Defence, Rafel Simó Vicens |
|---|---|
| Location | Henrik Dam Auditorium, Mærsk Tower, Blegdamsvej 3B, 2200 København N |
| Country/Territory | Denmark |
| City | Copenhagen |
| Period | 25/04/2019 → 25/04/2019 |
Keywords
- Faculty of Health and Medical Sciences
- atrial fibrillation
- Arrhythmia
- small conductance calcium-activated potassium channels
- kcnn2
- kcnn3
- kcnn1
- negative allosteric modulator
- Inhibitor
- ap14145
- ns8593
- apamin
- acesion pharma
- kcnn4
- bbp
- 2,6-bis(2-benzimidazolyl)pyridine
- N-(2-{[(1R)-1-[3-(trifluoromethyl)phenyl]ethyl]amino}-1H-1,3-benzodiazol-4-yl) acetamide
- Antiarrhythmic drugs
- CAM
- calmodulin
