Key result
AP14145, a novel negative allosteric modulator of KCa2 channels, significantly prolonged the atrial effective refractory period in rats from 31 ms to 58 ms at 5 mg/kg without triggering acute CNS effects in mice.
Absolute Event Rate: 58% vs 31%
p-value: p=<0.05
AP14145 is a novel negative allosteric modulator of KCa2 channels that prolongs atrial refractoriness in rats without acute CNS effects, highlighting its potential for atrial fibrillation drug development.
May guide KCa2-targeted AF drug development; leaves open translation from rodent models to humans.
Background and Purpose Small conductance calcium‐activated potassium (KCa2) channels represent a promising atrial‐selective target for treatment of atrial fibrillation. Here, we establish the mechanism of KCa2 channel inhibition by the new compound AP14145. Experimental Approach Using site‐directed mutagenesis, binding determinants for AP14145 inhibition were explored. AP14145 selectivity and mechanism of action were investigated by patch‐clamp recordings of heterologously expressed KCa2 channels. The biological efficacy of AP14145 was assessed by measuring atrial effective refractory period (AERP) prolongation in anaesthetized rats, and a beam walk test was performed in mice to determine acute CNS‐related effects of the drug. Key Results AP14145 was found to be an equipotent negative allosteric modulator of KCa2.2 and KCa2.3 channels (IC50 = 1.1 ± 0.3 μM). The presence of AP14145 (10 μM) increased the EC50 of Ca2+ on KCa2.3 channels from 0.36 ± 0.02 to 1.2 ± 0.1 μM. The inhibitory effect strongly depended on two amino acids, S508 and A533 in the channel. AP14145 concentration‐dependently prolonged AERP in rats. Moreover, AP14145 (10 mg·kg−1) did not trigger any apparent CNS effects in mice. Conclusions and Implications AP14145 is a negative allosteric modulator of KCa2.2 and KCa2.3 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 KCa2 channels are inhibited, at the molecular level, will help further development of drugs targeting KCa2 channels.
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Simó‐Vicens et al. (2017) studied Atrial Fibrillation (Preclinical). AP14145 vs. Vehicle was evaluated on Atrial effective refractory period (AERP) 1 minute after 5 mg/kg bolus injection (p=<0.05). AP14145, a novel negative allosteric modulator of KCa2 channels, significantly prolonged the atrial effective refractory period in rats from 31 ms to 58 ms at 5 mg/kg without triggering acute CNS effects in mice.
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