Selective and brain-penetrant HCN1 inhibitors reveal links between synaptic integration, cortical function, and working memory.

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 neurophysiology and exploiting its therapeutic potential has been hampered by minimally selective antagonists with poor potency and limited in vivo efficiency. Using automated electrophysiology in a small-molecule library screen and chemical 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 physiology 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.

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Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests During the course of this study, E.H., M.H., M.W., R.H., D.W., R.W., J.-Y.W., A.G., P.S., A.G.-W., R.G., M.R., A.D., S.R., E.C.O., B.B., and B.J.H. are or were employees at F. Hoffmann-La Roche Ltd. and may be shareholders of F. Hoffmann-La Roche Ltd; M.P. and J.-F.R. are employees at Axxam. W.H. is an employee at WuXi AppTec (Wuhan) Co. A patent application (WO2021110574) was filed that includes some of the data described in this article.