VK-II-86

VK-II-86 is an inhibitor of store-overload-induced calcium release (SOICR) and a derivative of carvedilol (Item No. 15418).¹ It inhibits SOICR in HEK293 cells expressing the ryanodine receptor 2 (RyR2) R4496C (RyR2^R4496C) mutation (IC₅₀ = 16.8 µM), a mutation that results in spontaneous calcium release from the endoplasmic reticulum. VK-II-86 (1 µM) inhibits the inward-rectifier potassium channel 2.1 (K_ir2.1), cardiac late sodium current (late I_Na), and L-type calcium current (I_Ca) in isolated canine cardiomyocytes and delayed-rectifier potassium current (I_Kr) in HEK293 cells expressing human-ether-a-go-go (hERG), also known as K_v11.1, in hypokalaemic, but not normokalaemic, conditions.² It is also an antagonist of toll-like receptor 4 (TLR4; IC₅₀ = 32.55 µM in HEK293 cells expressing the human receptor) and inhibits hyperpolarization-activated cyclic nucleotide gated potassium channel 4 (HCN4) in COS-7 cells expressing HCN4 when used at a concentration of 10 µM.³ VK-II-86 prevents hypokalaemia-induced ventricular arrhythmia in isolated Langendorff-perfused mouse hearts.² Unlike the β-adrenergic receptor antagonist carvedilol, it does not reverse isoproterenol-induced increases in heart rate or decrease resting heart rate in RyR2^R4496C-expressing mice.⁴

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1. Smith, C.D., Wang, A., Vembaiyan, K., et al. Novel carvedilol analogues that suppress store-overload-induced Ca²⁺ release. J. Med. Chem. 56(21), 8625-8655 (2013).

2. Robinson, V.M., Alsalahat, I., Freeman, S., et al. A carvedilol analogue, VK-II-86, prevents hypokalaemia-induced ventricular arrhythmia through novel multi-channel effects. Br. J. Pharmacol. 179(11), 2713-2732 (2022).

3. Xu, Y., Chen, S., Cao, Y., et al. Discovery of novel small molecule TLR4 inhibitors as potent anti-inflammatory agents. Eur. J. Med. Chem. 154, 253-266 (2018).

4. Zhou, Q., Xiao, J., Jiang, D., et al. Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca²⁺ release. Nat. Med. 17(8), 1003-1009 (2011).