AI Summary
The article discusses the development of N-sulfonylphenoxazines as new inhibitors for N-type calcium channels in the treatment of neuropathic pain. These compounds were synthesized and tested for their effectiveness in inhibiting CaV2.2 and CaV3.2 neuronal ion channels, with some showing low micromolar activity. The best performing compounds are likely to be able to penetrate the blood-brain barrier. Additionally, the N-sulfonylphenoxazines were found to be more stable in rat plasma compared to previous inhibitors, and relatively stable in an in vitro liver microsome metabolism model. Molecular modeling was also used to understand how these inhibitors interact with the calcium channel at a molecular level.
Neuropathic pain is a type of chronic pain, usually caused by nerve damage, that responds poorly to traditional pain therapies. The N-type calcium channel (CaV2.2) is a well-validated pharmacological target to treat this condition. In order to further improve the inhibition of the N-type calcium channel relative to previously described inhibitors, and also address their problematic instability in blood plasma, the development of N-sulfonylphenoxazines as new calcium channel inhibitors was pursued. A series of N-sulfonylphenoxazines bearing ammonium side chains were synthesised and tested for their ability to inhibit both CaV2.2 and CaV3.2 (T-type) neuronal ion channels. Compounds with low micromolar activity in CaV2.2 were identified, equivalent to the most effective reported for this class of bioactive, and calculations based on their physical and chemical characteristics suggest that the best performing compounds have a high likelihood of being able to penetrate the blood-brain barrier. Representative N-sulfonylphenoxazines were tested for their stability in rat plasma and were found to be much more resilient than the previously reported N-acyl analogues. These compounds were also found to be relatively stable in an in vitro liver microsome metabolism model, the first time that this has been investigated for this class of compound. Finally, molecular modelling of the CaV2.2 channel was used to gain an understanding of the mode of action of these inhibitors at a molecular level. They appear to bind in a part of the channel, in and above its selectivity filter, in a way that hinders its ability to undergo the conformational