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8.B.45.  The Isothiourea Derivative, KB-R7943 (KB-R7943) Family 

KB-R7943, an isothiourea derivative, is widely used as a pharmacological inhibitor of the reverse sodium-calcium exchanger (NCX). It has neuroprotective and analgesic effects in animal models. Sun et al. 2023 investigated whether KB-R7943 modulates acid-sensing ion channels (ASICs), a group of proton-gated cation channels implicated in the pathophysiology of various neurological disorders. KB-R7943 irreversibly inhibits homomeric ASIC1a channels and  also reversibly inhibits homomeric ASIC2a and ASIC3 channels. Both the transient and sustained current components of ASIC3 are inhibited. KB-R7943 inhibits ASICs in primary cultured peripheral and central neurons, inhibits the ASIC-like currents in mouse dorsal root ganglion (DRG) neurons and the ASIC1a-like currents in mouse cortical neurons. The inhibition of the ASIC1a-like current is use-dependent and unrelated to its effect on NCX since neither of the other two well-characterized NCX inhibitors, including SEA0400 and SN-6, showed an effect on ASIC. The isothiourea group, which is lacking in other structurally related analogs that do not affect ASIC1a-like current, may serve as a critical functional group. Thus, KB-R7943 is a new ASIC inhibitor. It provides a novel pharmacological tool for the investigation of the functions of ASICs and could serve as a lead compound for developing small-molecule drugs for treating ASIC-related disorders (Sun et al. 2023). KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate) is a potent  Na+/Ca2+ exchange (NCX) inhibitor that is 3-fold more inhibitory to NCX3 than to NCX1 (Iwamoto et al. 2001). It may also inhibit Ca2+ channels and the mitochondrial Ca2+ uniporter (Namekata et al. 2020).


References associated with 8.B.45 family:

Iwamoto, T., S. Kita, A. Uehara, Y. Inoue, Y. Taniguchi, I. Imanaga, and M. Shigekawa. (2001). Structural domains influencing sensitivity to isothiourea derivative inhibitor KB-R7943 in cardiac Nna(+)/Ca2+ exchanger. Mol Pharmacol 59: 524-531. 11179448
Namekata, I., R. Odaka, S. Hamaguchi, and H. Tanaka. (2020). KB-R7943 Inhibits the Mitochondrial Ca Uniporter but Not Na-Ca Exchanger in Cardiomyocyte-Derived H9c2 Cells. Biol Pharm Bull 43: 1993-1996. 33028749
Sun, H.W., X.P. Chu, R.P. Simon, Z.G. Xiong, and T.D. Leng. (2023). Inhibition of Acid-Sensing Ion Channels by KB-R7943, a Reverse Na/Ca Exchanger Inhibitor. Biomolecules 13:. 36979442