Electropharmacological Profiles of NTC-801, a Novel Selective Acetylcholine-Activated K+ Channel Blocker

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Introduction: The acetylcholine-activated K+ current (IK,ACh or GIRK1/4 current) is a target for atrial-specific antiarrhythmic therapy. This study examined the electropharmacological profile of a novel IK,ACh blocker, NTC-801. Methods: The IK,ACh inhibitory effects of NTC-801 were examined using guinea pig (GP) atrial cells and Xenopus oocytes. The effects on action potential (AP) were examined using GP atrial and ventricular cells and papillary muscles. The binding assays were used to determine the affinities to receptors. Results: NTC-801 inhibited IK,ACh induced by carbachol, adenosine or GTPγS in GP atrial cells with IC50 of around 6 nmol/L. The inhibitory effect of NTC-801 on IK,ACh was >1000-fold more potent than those on muscarinic M2 receptor, adenosine A1 receptor and other cardiac currents including IKr, INa and ICaL. NTC-801 inhibited GIRK1/4 current 34-fold more potently than GIRK1/2 current in Xenopus oocytes. NTC-801 reversed the AP shortening induced by carbachol or adenosine in GP atrial cells, but had little effects on AP of GP ventricular cells and papillary muscles. Conclusions: NTC-801 is the first synthetic compound that selectively inhibits IK,ACh over other cardiac currents. NTC-801 also showed selectivity for GIRK1/4 (cardiac-type) over GIRK1/2 (brain-type) currents. These results suggest that NTC-801 may be a unique atrial-specific antiarrhythmic drug for the atrial fibrillation treatment.