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Current Topics in Medicinal Chemistry


ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

HCN Channels Modulators: The Need for Selectivity

Author(s): Maria Novella Romanelli, Laura Sartiani, Alessio Masi, Guido Mannaioni, Dina Manetti, Alessandro Mugelli and Elisabetta Cerbai

Volume 16, Issue 16, 2016

Page: [1764 - 1791] Pages: 28

DOI: 10.2174/1568026616999160315130832

open access plus


Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, the molecular correlate of the hyperpolarization-activated current (If/Ih), are membrane proteins which play an important role in several physiological processes and various pathological conditions. In the Sino Atrial Node (SAN) HCN4 is the target of ivabradine, a bradycardic agent that is, at the moment, the only drug which specifically blocks If. Nevertheless, several other pharmacological agents have been shown to modulate HCN channels, a property that may contribute to their therapeutic activity and/or to their side effects.

HCN channels are considered potential targets for developing drugs to treat several important pathologies, but a major issue in this field is the discovery of isoform-selective compounds, owing to the wide distribution of these proteins into the central and peripheral nervous systems, heart and other peripheral tissues. This survey is focused on the compounds that have been shown, or have been designed, to interact with HCN channels and on their binding sites, with the aim to summarize current knowledge and possibly to unveil useful information to design new potent and selective modulators.

Keywords: HCN channels, Hyperpolarization-activated current, Ivabradine, Drug design, Selectivity, Atrial and Ventricular arrhythmia, Atrial fibrillation, Parkinson’s disease.

Graphical Abstract

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