Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Dec 19;10(1):10.
doi: 10.3390/biom10010010.

Challenges Faced with Small Molecular Modulators of Potassium Current Channel Isoform Kv1.5

Zefeng Zhao  1   2 , Songsong Ruan  1   2 , Xiaoming Ma  1   2 , Qian Feng  1   2 , Zhuosong Xie  1   2 , Zhuang Nie  1   2 , Peinan Fan  1   2 , Mingcheng Qian  3   4 , Xirui He  5 , Shaoping Wu  1   2 , Yongmin Zhang  1   2   6 , Xiaohui Zheng  1   2
Affiliations
Review

Challenges Faced with Small Molecular Modulators of Potassium Current Channel Isoform Kv1.5

Zefeng Zhao et al. Biomolecules. .

Abstract

The voltage-gated potassium channel Kv1.5, which mediates the cardiac ultra-rapid delayed-rectifier (IKur) current in human cells, has a crucial role in atrial fibrillation. Therefore, the design of selective Kv1.5 modulators is essential for the treatment of pathophysiological conditions involving Kv1.5 activity. This review summarizes the progress of molecular structures and the functionality of different types of Kv1.5 modulators, with a focus on clinical cardiovascular drugs and a number of active natural products, through a summarization of 96 compounds currently widely used. Furthermore, we also discuss the contributions of Kv1.5 and the regulation of the structure-activity relationship (SAR) of synthetic Kv1.5 inhibitors in human pathophysiology. SAR analysis is regarded as a useful strategy in structural elucidation, as it relates to the characteristics that improve compounds targeting Kv1.5. Herein, we present previous studies regarding the structural, pharmacological, and SAR information of the Kv1.5 modulator, through which we can assist in identifying and designing potent and specific Kv1.5 inhibitors in the treatment of diseases involving Kv1.5 activity.

Keywords: KCNA5; Kv1.5; SAR; modulators; potassium channel.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(A) Schematic representation of the hKv1.5 α-subunit with the sequence of the S6 region listed. (B) Homologous model of Kv1.5 (Q61672) with 67.2% similarity for the Kv1.5 sequence, obtained from the SWISS-MODEL database; some of the residues are slightly different from those published in previous research. (C) Basic Local Alignment Search Tool (BLAST) result of KCNA5_HUMAN (P22460), obtained from the NCBI BLAST+ database. (D) Sequence alignment ofKCNA1_HUMAN (Q09470), KCNA3_HUMAN (P22001), KCNA2_HUMAN (P16389), and KCNA5_HUMAN (P22460), acquired from the ESPript database.
Figure 2
Figure 2
(A) Pharmacophore model of vernakalant (cyan ball: hydrophobic center; yellow ball: aromatic center; green ball: hydrogen bond receptor; pink ball: hydrogen bond donor; red ball: ionizable positive center); (B) potential binding domain of vernakalant in Kv1.5 (H-bond is expressed as green dashed).
Figure 3
Figure 3
Biphenyl derivatives.
Figure 4
Figure 4
Anthranilic amides.
Figure 5
Figure 5
Phenoxyalkoxypsoralen analogues.
Figure 6
Figure 6
(2-phenethyl-2H-1,2,3-triazol-4-yl)(phenyl) methanones.
Figure 7
Figure 7
Tetrahydroindolone-derived carbamates.
Figure 8
Figure 8
Tetrahydroindolone-derived semicarbazones.
Figure 9
Figure 9
Diisopropyl amide derivatives.
Figure 10
Figure 10
Isoquinoline-3-nitriles.
Figure 11
Figure 11
Psoralen derivatives.
Figure 12
Figure 12
Thiazolidine derivatives.
Figure 13
Figure 13
Benzopyran sulfonamides.
Figure 14
Figure 14
Thiazolidine derivatives.
Figure 15
Figure 15
Dihydropyrazolopyrimidine derivatives.
Figure 16
Figure 16
Aryl sulfonamido tetralin derivatives.
Figure 17
Figure 17
Structure-activity relationship (SAR) of imidazolidinone derivatives.
Figure 18
Figure 18
SAR of pyrazolodihydropyrimidines.
Figure 19
Figure 19
SAR of heteroarylsulfonamides.
Figure 20
Figure 20
SAR of dihydropyrazolo[1,5-a]pyrimidine derivatives.
Figure 21
Figure 21
SAR of trifluoromethylcyclohexyl triazole analogues.
Figure 22
Figure 22
SAR of indole derivatives.
Figure 23
Figure 23
SAR of diphenylphosphinic amides and diphenylphosphine oxides.
Figure 24
Figure 24
SAR of lactam sulfonamides.
Figure 25
Figure 25
SAR of phenethylaminoheterocycles.
Figure 26
Figure 26
SAR of 1-aryloxyethyl piperazine derivatives.
Figure 27
Figure 27
SAR of isoindolinones.
Figure 28
Figure 28
SAR of phenylquinazoline derivatives.
Figure 29
Figure 29
SAR of phenylquinazoline sulfonamide derivatives.
Figure 30
Figure 30
SAR of oroidin derivatives.
Figure 31
Figure 31
SAR of oroidin MK-1832.
Figure 32
Figure 32
SAR of 1,2-bis(aryl)ethane-1,2-diamines.
Figure 33
Figure 33
SAR of aplysiatoxin derivatives.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Milnes J.T., Madge D.J., Ford J.W. New pharmacological approaches to atrial fibrillation. Drug Discov. Today. 2012;17:654–659. doi: 10.1016/j.drudis.2012.02.007. - DOI - PubMed
    1. Amos G.J., Wettwer E., Metzger F., Li Q., Himmel H.M., Ravens U. Differences between outward currents of human atrial, and subepicardial ventricular myocytes. J. Physiol. 1996;491:31–50. doi: 10.1113/jphysiol.1996.sp021194. - DOI - PMC - PubMed
    1. Humphries E.S.A., Dart C. Neuronal and cardiovascular potassium channels as therapeutic drug targets: Promise and pitfalls. J. Biomol. Screen. 2015;20:1055–1073. doi: 10.1177/1087057115601677. - DOI - PMC - PubMed
    1. Kojima A., Ito Y., Ding W.-G., Kitagawa H., Matsuura H. Interaction of propofol with voltage-gated human Kv1.5 channel through specific amino acids within the pore region. Eur. J. Pharmacol. 2015;764:622–632. doi: 10.1016/j.ejphar.2015.08.007. - DOI - PubMed
    1. Nerbonne J.M., Kass R.S. Molecular physiology of cardiac repolarization. Physiol. Rev. 2005;85:1205–1253. doi: 10.1152/physrev.00002.2005. - DOI - PubMed

Publication types

MeSH terms