Targeting KCa3.1 Channels: The Anti-Inflammatory Potential of NS6180 in Rat Models of IBD

The KCa3.1 channel has been identified as a promising target for treating immune-related diseases. A newly discovered compound from a distinct chemical category of KCa3.1 inhibitors was evaluated for its ability to suppress immune reactions both in the laboratory and in living organisms.

The compound, designated as NS6180, was studied for its effectiveness and the specific molecular mechanism by which it acts on KCa3.1 channels. It was also tested for its selectivity towards other potential targets, its impact on T-cell activation, and its pharmacokinetic properties, as well as its capacity to manage inflammation in a rat model of inflammatory bowel disease (IBD) induced by 2,4-dinitrobenzene sulfonic acid.

NS6180 was found to inhibit human KCa3.1 channels at a concentration of 9 nanomolar, acting through specific amino acid residues T250 and V275, which are known to be sensitive to triarylmethanes like TRAM-34. It also showed similar potency in inhibiting KCa3.1 channels in erythrocytes from humans, mice, and rats, with an efficacy range of 15 to 20 nanomolar. Furthermore, NS6180 was able to suppress the proliferation of splenocytes from rats and mice at submicromolar concentrations and significantly reduced the production of IL-2 and IFN-γ, with less impact on IL-4 and TNF-α, and no effect on IL-17 production. The presence of KCa3.1 channels was confirmed in healthy colon tissue, with an increase observed in colitis conditions associated with immune cell infiltration. Notably, NS6180 demonstrated a reduction in colon inflammation and an improvement in body weight gain in rats, similar to the standard IBD drug sulfasalazine, despite its low plasma exposure.

In conclusion, NS6180 is a novel KCa3.1 channel inhibitor that has shown potential in mitigating experimental colitis, indicating that KCa3.1 channels could be viable targets for the pharmacological management of intestinal inflammation.