Dataset Information
NS6180, a new K(Ca) 3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease.
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ABSTRACT: Background and purpose
The K(Ca) 3.1 channel is a potential target for therapy of immune disease. We identified a compound from a new chemical class of K(Ca) 3.1 inhibitors and assessed in vitro and in vivo inhibition of immune responses.Experimental approach
We characterized the benzothiazinone NS6180 (4-[[3-(trifluoromethyl)phenyl]methyl]-2H-1,4-benzothiazin-3(4H)-one) with respect to potency and molecular site of action on K(Ca) 3.1 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 K(Ca) 3.1 channels (IC(50) = 9?nM) via T250 and V275, the same amino acid residues conferring sensitivity to triarylmethanes such as like TRAM-34. NS6180 inhibited endogenously expressed K(Ca) 3.1 channels in human, mouse and rat erythrocytes, with similar potencies (15-20?nM). NS6180 suppressed rat and mouse splenocyte proliferation at submicrolar concentrations and potently inhibited IL-2 and IFN-? production, while exerting smaller effects on IL-4 and TNF-? and no effect on IL-17 production. Antibody staining showed K(Ca) 3.1 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 K(Ca) 3.1 channel inhibitors which inhibited experimental colitis, suggesting K(Ca) 3.1 channels as targets for pharmacological control of intestinal inflammation.
SUBMITTER: Strobæk D
PROVIDER: S-EPMC3572569 | biostudies-literature | 2013 Jan
REPOSITORIES: biostudies-literature
Publications
NS6180, a new K(Ca) 3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease.
British journal of pharmacology 20130101 2
<h4>Background and purpose</h4>The K(Ca) 3.1 channel is a potential target for therapy of immune disease. We identified a compound from a new chemical class of K(Ca) 3.1 inhibitors and assessed in vitro and in vivo inhibition of immune responses.<h4>Experimental approach</h4>We characterized the benzothiazinone NS6180 (4-[[3-(trifluoromethyl)phenyl]methyl]-2H-1,4-benzothiazin-3(4H)-one) with respect to potency and molecular site of action on K(Ca) 3.1 channels, selectivity towards other targets, ...[more]