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

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

  • Cell Chem Biol. 2024 Mar 21;31(3):577-592.e23. doi: 10.1016/j.chembiol.2023.11.004.
Eva Harde 1,  Markus Hierl 2,  Michael Weber 3,  David Waiz 4,  Roger Wyler 3,  Jean-Yves Wach 2,  Rachel Haab 3,  Anja Gundlfinger 3,  Weiping He 5,  Patrick Schnider 2,  Manuel Paina 6,  Jean-Francois Rolland 6,  Andrea Greiter-Wilke 4,  Rodolfo Gasser 4,  Michael Reutlinger 2,  Amanda Dupont 2,  Sonia Roberts 4,  Eoin C O'Connor 7,  Björn Bartels 8,  Benjamin J Hall 3
Affiliations

Affiliations

  • 1 Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland. Electronic address: eva.harde@roche.com.
  • 2 Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
  • 3 Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
  • 4 Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
  • 5 WuXi AppTec (Wuhan) Co., Ltd, 666 Gaoxin Road, Wuhan East Lake High-Tech Development Zone, Wuhan, Huibei, China.
  • 6 Axxam SpA, Bresso (Milano), Italy.
  • 7 Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland. Electronic address: eoin.oconnor@roche.com.
  • 8 Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland. Electronic address: bjoern.bartels@roche.com.
PMID: 38042151 DOI: 10.1016/j.chembiol.2023.11.004
Abstract

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.

Keywords

HCN; cardiovascular; cognition; electrophysiology; epilepsy; inhibitor; schizophrenia; screen; touchscree.

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