Author: Gasser, Rodolfo ; Paina, Manuel ; Weber, Michael ; He, Weiping ; Roberts, Sonia ; Wyler, Roger ; Gundlfinger, Anja ; Reutlinger, Michael ; Rolland, Jean-Francois ; Waiz, David ; Schnider, Patrick ; O′Connor, Eoin C. ; Greiter-Wilke, Andrea ; Haab, Rachel ; Hierl, Markus ; Hall, Benjamin J. ; Bartels, Bjorn ; Dupont, Amanda ; Harde, Eva ; Wach, Jean-Yves
Hyperpolarization-activated and cyclic-nucleotide-gated 1 (HCN1) ion channels are proposed to be critical for cognitive function through regulation of synaptic integration.However, resolving the precise role of HCN1 in neurophysiol. and exploiting its therapeutic potential has been hampered by minimally selective antagonists with poor potency and limited in vivo efficiency.Using automated electrophysiol. in a small-mol. library screen and chem. optimization, we identified a primary carboxamide series of potent and selective HCN1 inhibitors with a distinct mode of action.In cognition-relevant brain circuits, selective inhibition of native HCN1 produced on-target effects, including enhanced excitatory postsynaptic potential summation, while administration of a selective HCN1 inhibitor to rats recovered decrement working memory.Unlike prior non-selective HCN antagonists, selective HCN1 inhibition did not alter cardiac physiol. in human atrial cardiomyocytes or in rats.Collectively, selective HCN1 inhibitors described herein unmask HCN1 as a potential target for the treatment of cognitive dysfunction in brain disorders.