التفاصيل البيبلوغرافية
| العنوان: |
NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease. |
| المؤلفون: |
Strøbæk, D, Brown, DT, Jenkins, DP, Chen, Y ‐ J, Coleman, N, Ando, Y, Chiu, P, Jørgensen, S, Demnitz, J, Wulff, H, Christophersen, P |
| المصدر: |
British Journal of Pharmacology; Jan2013, Vol. 168 Issue 2, p432-444, 13p, 1 Color Photograph, 1 Diagram, 6 Graphs |
| مصطلحات موضوعية: |
T cells, INFLAMMATORY bowel diseases, LABORATORY rats, IMMUNOLOGIC diseases, IMMUNE response, TRIFLUOROMETHYL compounds, THERAPEUTICS |
| مستخلص: |
Background and Purpose The KCa3.1 channel is a potential target for therapy of immune disease. We identified a compound from a new chemical class of KCa3.1 inhibitors and assessed in vitro and in vivo inhibition of immune responses. Experimental Approach We characterized the benzothiazinone NS6180 (4-[[3-(trifluoromethyl)phenyl]methyl]-2 H-1,4-benzothiazin-3(4 H)-one) with respect to potency and molecular site of action on KCa3.1 channels, selectivity towards other targets, effects on T-cell activation as well as pharmacokinetics and inflammation control in colitis induced by 2,4-dinitrobenzene sulfonic acid, a rat model of inflammatory bowel disease ( IBD). Key Results NS6180 inhibited cloned human KCa3.1 channels ( IC50 = 9 n M) via T250 and V275, the same amino acid residues conferring sensitivity to triarylmethanes such as like TRAM-34. NS6180 inhibited endogenously expressed KCa3.1 channels in human, mouse and rat erythrocytes, with similar potencies (15-20 n M). NS6180 suppressed rat and mouse splenocyte proliferation at submicrolar concentrations and potently inhibited IL-2 and IFN-γ production, while exerting smaller effects on IL-4 and TNF-α and no effect on IL-17 production. Antibody staining showed KCa3.1 channels in healthy colon and strong up-regulation in association with infiltrating immune cells after induction of colitis. Despite poor plasma exposure, NS6180 (3 and 10 mg·kg−1 b.i.d.) dampened colon inflammation and improved body weight gain as effectively as the standard IBD drug sulfasalazine (300 mg·kg−1 q.d.). Conclusions and Implications NS6180 represents a novel class of KCa3.1 channel inhibitors which inhibited experimental colitis, suggesting KCa3.1 channels as targets for pharmacological control of intestinal inflammation. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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