Akihiko Sunami¹ and Tatsuo Munakata²
¹School of Pharmacy, Department of Pharmaceutical Sciences, International University of Health and Welfare, Otawara, Tochigi, Japan
²School of Pharmacy at Fukuoka, Department of Pharmaceutical Sciences, International University of Health and Welfare, Okawa, Fukuoka, Japan

Part of the book: Advances in Health and Disease. Volume 63

Abstract

Voltage-gated sodium channels (Navs) are membrane proteins responsible for the generation of action potentials in nerves, skeletal muscles and the heart. Accordingly, Navs are the major targets for local anesthetic, antiepileptic and antiarrhythmic drugs. Recent structural studies using cryoelectron microscopy (cryo-EM) visualized various isoforms of Navs (Nav1.1, Nav1.2, Nav1.4, Nav1.5 and Nav1.7) at high[1]resolution. These studies have greatly advanced our understanding of channel architecture, voltage-sensing, fast inactivation, ion selectivity and channelopathy. The structures of Nav1.5, the primary Nav in the heart, have also been determined in a complex with class I antiarrhythmic drugs. Quinidine (Ia agent) and flecainide (Ic agent) interact with the key residue, F1760 on domain IV (DIV) S6 in the inactivated channel, but directly do not interact with Y1767. Although quinidine is engaged within the central cavity, flecainide is away from the central axis. On the other hand, propafenone (Ic agent) interacts with F1760 and Y1767 in the open channel. These three drugs are positioned right beneath the selectivity filter or the positively charged amino residues of these drugs which point toward the selectivity filter, and these drugs likely block the ion conduction pathway. Quinidine facilitates gate closing through an allosteric mechanism, but propafenone leaves the intracellular gate open. Although these studies reveal the accurate binding pose of these drugs in a single functional state, that is, the open or inactivated state of Nav1.5, it has been unknown what poses the drugs adopt state-dependently and isoform-dependently. Our previous structural modeling and docking of the mexiletine (Ib agent) in the open and resting or closed states of Nav1.5 showed that mexiletine occurs in the upper part in the pore in the open state and lower in the closed state. High-affinity binding of mexiletine in the open state of Nav1.5 is caused by a π-π interaction with F1760, whereas mexiletine is located away from the corresponding Phe (F1764) in the open state of Nav1.2, which has a lower affinity for mexiletine than Nav1.5. These structural observations of mexiletine block are consistent with the experimental data. This review will focus on the structural pharmacology of antiarrhythmic drug interactions with Nav1.5 and other Navs from the cryo-EM structures of Nav1.5 with the drugs, fenestrations forming hydrophobic pathways and the structural basis for isoform differences in the state-dependent block.

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