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Class I antiarrhythmic drugs are used to treat various types of arrhythmias or irregular heart rhythms. These drugs block the sodium (Na+) channels in the cardiac cells, thereby affecting the movement of electrical impulses across the heart. Class I antiarrhythmic drugs are divided into three subgroups: Class IA, Class IB, and Class IC, each with distinct mechanisms of action and effects on the heart.
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Indirect-acting cholinergic agonists are agents that interact with the acetylcholinesterase enzyme in the synaptic cleft, preventing the breakdown of acetylcholine into choline and acetate. Consequently, the concentration of acetylcholine in the synaptic cleft increases. These agonists can be classified into reversible and irreversible inhibitors based on their duration of action.
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Heterocyclic amines, where the N atom is a part of an alicyclic system, are similar in basicity to alkylamines. Interestingly, the heterocyclic amine having a nitrogen atom as part of an aromatic ring has much less basicity than its corresponding alicyclic counterpart. For this reason, as presented in Figure 1, piperidine (pKb = 2.8) is significantly more basic than pyridine (pKb = 8.8).
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4-(Azolyl)-Benzamidines as a Novel Chemotype for ASIC1a Inhibitors.

Maksym Platonov1,2, Oleksandr Maximyuk3, Alexey Rayevsky1,2,4

  • 1Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Zabolotnogo Str., 150, 03143 Kyiv, Ukraine.

International Journal of Molecular Sciences
|April 13, 2024
PubMed
Summary

Acid-sensing ion channels (ASICs) are crucial for neuronal function and disease. This study reveals the structural basis of ASIC1a inhibition by amiloride, identifying new potential therapeutics for neurological disorders.

Keywords:
acid-sensitive ion channelautomated patch clampdrug discoveryscreening assayvirtual screening

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Acid-sensing ion channels (ASICs) are proton-gated cation channels vital for neuronal functions, including learning, memory, and pain perception.
  • ASIC1a, a key isoform in the central nervous system, is implicated in neurological disorders like stroke, epilepsy, and pain, making it a therapeutic target.
  • Understanding ASIC regulation is crucial, yet remains poorly understood, particularly the mechanisms of channel inactivation and inhibition.

Purpose of the Study:

  • To analyze the channel inactivation process of ASIC1 using molecular dynamics simulations and crystal structures.
  • To investigate the structural basis of amiloride inhibition on ASIC1a, focusing on its interaction with the ion pore in the open state.
  • To identify novel ASIC inhibitors through high-throughput virtual screening of the Enamine chemical library.

Main Methods:

  • Molecular dynamics (MD) simulations were used to analyze ASIC1 inactivation and amiloride binding.
  • Molecular docking and high-throughput virtual screening were employed to identify potential ASIC inhibitors from the Enamine library.
  • Electrophysiological assays were conducted to validate the inhibitory activity of identified compounds.

Main Results:

  • The study elucidated the structural mechanisms underlying ASIC1 channel inactivation and amiloride's inhibitory action.
  • In silico approaches visualized amiloride's interaction with the ASIC1a ion pore in its open state.
  • Virtual screening identified three hit compounds with significant ASIC inhibitory activity, confirmed by electrophysiological assays.

Conclusions:

  • ASIC1a structure and function are complex, with specific regions like the acidic pocket regulating gating.
  • Amiloride's inhibition mechanism was detailed, providing insights for designing more effective ASIC modulators.
  • The identified hit compounds represent promising leads for developing therapeutics targeting ASIC-related neurological disorders.