Hyperpolarization-activated cyclic nucleotide gate (HCN) channels are proteins present on the surface of cardiac cells. Following binding to the cyclic molecule cAMP, HCN channels become active and generate a funny current, namely an electric impulse that stimulates the heart to contract. By doing so, HCN channels control the frequency of heartbeats and, therefore, they constitute an attractive pharmacological target to modulate the cardiac function.

Anna Moroni, University of Milan, Italy, and co-workers identified a compound that inhibits HCN channels in a powerful and selective manner. The researchers demonstrated that N′-biphenyl-2-yl-N-[1- (3-cyanobenzyl)piperidin-4-yl]-N-(pyridin-3-ylmethyl)urea (biphenyl urea) antagonizes cAMP, thereby preventing the activation of HCN channels and the generation of the funny current.

Biphenyl urea might, therefore, be a novel drug to lower the frequency of heartbeats in patients affected by cardiovascular problems such as high blood pressure.

• Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness,
  Marco Lolicato, Annalisa Bucchi, Cristina Arrigoni, Stefano Zucca, Marco Nardini, Indra Schroeder, Katie Simmons, Marco Aquila, Dario DiFrancesco, Martino Bolognesi, Frank Schwede, Dmitry Kashin, Colin W G Fishwick, A Peter Johnson, Gerhard Thiel, Anna Moroni,
  Nature Chemical Biology 2014, 10, 457–462.
  DOI: 10.1038/nchembio.1521