A new negative allosteric modulator, AP14145, for the study of small conductance calcium‐activated potassium (K_Ca2) channels

Abstract

AP14145 is a negative allosteric modulator of K 2.2 and K 2.3 channels that shifted the calcium dependence of channel activation, an effect strongly dependent on two identified amino acids. AP14145 prolonged AERP in rats and did not trigger any acute CNS effects in mice. The understanding of how K 2 channels are inhibited, at the molecular level, will help further development of drugs targeting K 2 channels.

2,6-Bis(2-Benzimidazolyl)Pyridine (BBP) Is a Potent and Selective Inhibitor of Small Conductance Calcium-Activated Potassium (SK) Channels

“…Within the calcium-activated potassium channels, it was found that the IK channel was not affected by BBP 1 μM (Figures 3A,B) whereas BK channel was inhibited by 19 ± 6% (Figure 4C), an inhibitory effect 4.8-fold lower than on any SK currents. Interestingly, this relation between BK and SK channels has also been observed for the allosteric modulator AP14145 (Simó-Vicens et al, 2017a). In the case of voltage-activated potassium channels, none of the six tested currents (K ir 2.1, K ir 3.1+K ir 3.4, K v 1.5, K v 4.3/K CHIP 2, K v 7.1/KCNE1, hERG) were significantly affected by BBP 10 μM, except for hERG, which was reduced by 19 ± 3% (Figure 6).…”

“…In addition, compounds may not be pharmacologically well characterized and with sufficient SK channel potency or general selectivity. Moreover, expansion of SK channels research, has further challenged currently available pharmacological tools which have been confronted with insensitive heteromeric channels (Hancock et al, 2015), difficult to access intracellular locations (Krabbendam et al, 2018), unexpected inhibitory effects (Voos et al, 2017), and intracellular calcium dependence (Strøbæk et al, 2006; Simó-Vicens et al, 2017a).…”

“…This interest has prompted the development of new molecules to both study and therapeutically target these channels. Since the discovery of apamin, a neurotoxin extracted from bee venom and the first specific SK inhibitor described (Habermann, 1984), the lists of both SK channel activators and inhibitors have grown (Weatherall et al, 2010; Christophersen and Wulff, 2015), including most recently the negative allosteric modulator AP14145 (Diness et al, 2017; Simó-Vicens et al, 2017a) and the natural flavone acacetin (Chen et al, 2017). However, some of these compounds may be difficult to access and/or use for a number of reasons such as low potency, incomplete pharmacological characterization or commercial unavailability.…”

Concomitant SK current activation and sodium current inhibition cause J wave syndrome

“…Unfortunately, apamin cannot be used clinically due to its neurotoxicity. AP14145, a newly synthesized I KAS negative modulator (37), might be a promising candidate for future use in JWS. Amiodarone suppresses I KAS at its therapeutic concentration (10-20 μmol/l) (38).…”

The KCa2 Channel Inhibitor AP30663 Selectively Increases Atrial Refractoriness, Converts Vernakalant-Resistant Atrial Fibrillation and Prevents Its Reinduction in Conscious Pigs

“…The small molecule AP30663 selectively inhibits K Ca 2 channels thereby diminishing the current mediated by them, I KCa (Bentzen et al, 2020). Other small-molecule K Ca 2 channel inhibitors give rise to adverse central nervous effects such as vomiting and tremors (Diness et al, 2017;Simó-Vicens et al, 2017), but this does not seem to be the case with AP30663.…”