Abstract
Atrial fibrillation (AF) is the most common clinical sustained arrhythmia; clinical therapeutic drugs have low atrial selectivity and might cause more severe ventricle arrhythmias while stopping AF. As an anti-AF drug target with high selectivity on the atrial muscle cells, the undetermined crystal structure of Kv1.5 potassium channel impeded further new drug development. Herein, with the simulated 3D structure of Kv1.5 as the drug target, a series of 3-morpholine linked aromatic amino substituted 1H-indoles as novel Kv1.5 channel inhibitors were designed and synthesized based on target–ligand interaction analysis. The synthesis route was practical, starting from commercially available material, and the chemical structures of target compounds were characterized. It was indicated that compounds T16 and T5 (100 μM) exhibited favorable inhibitory activity against the Kv1.5 channel with an inhibition rate of 70.8 and 57.5% using a patch clamp technique. All compounds did not exhibit off-target effects against other drug targets, which denoted some selectivity on the Kv1.5 channel. Interestingly, twelve compounds exhibited favorable vasodilation activity on pre-contracted arterial rings in vitro using KCl or phenylephrine (PE) by a Myograph. The vasodilation rates of compounds T16 and T4 (100 μM) even reached over 90%, which would provide potential lead compounds for both anti-AF and anti-hypertension new drug development.
Highlights
As the most common clinical sustained arrhythmia, atrial fibrillation (AF) presents with a wide spectrum of symptoms and severity (Lau et al, 2019)
3.1.1 Molecular Skeleton Design Based on target–ligand interaction and structure-activity analysis of traditional inhibitors and its simulated 3D structure of target Kv1.5, a series of compounds (T1–T16), containing both morpholine and 1H-indole linked with a chain-like structure (-N(CH2)nO-) in one molecule, were designed to enhance therapeutic effects of the anti-AF drugs (Figure 1)
The simulated 3D structure of the transmembrane region of the Kv1.5 channel was built using the homology modeling technique based on the transmembrane region of the Kv1.2 channel (PDB ID: 2A79), which reached over 70% amino acid sequence homology with the Kv1.5 channel
Summary
As the most common clinical sustained arrhythmia, atrial fibrillation (AF) presents with a wide spectrum of symptoms and severity (Lau et al, 2019). There are many therapeutic drugs for clinically treating AF, such as Dofetilide, Aminodarone, Sotalol, Propafenone, flecainide, etc. These drugs have low atrial selectivity while stopping AF, which could often cause severe adverse effects such as ventricle arrhythmias (e.g., life-threatening TdP) (Ang et al, 2020). An ideal drug to treat AF should have high selectivity on the atrial muscle cells, which could terminate or postpone the occurrence of AF without affecting or prolonging the Q-T interval or the negative inotropic action to ensure the highly effective safety (Guo et al, 2016; Zimetbaum, 2017). The inhibitor of the Kv1.5 channel might selectively prolong the effective refractory period (ERP) of the atrium to terminate AF (Tamargo et al, 2009)
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