Selective HCN1 inhibitors enhanced excitatory postsynaptic potential summation and recovered working memory in rats without altering cardiac physiology.
Do selective HCN1 inhibitors improve working memory without altering cardiac physiology in preclinical models?
Selective HCN1 inhibitors improve working memory in rats without the cardiac side effects seen with non-selective HCN antagonists, highlighting their potential for treating cognitive dysfunction.
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.
Harde et al. (Fri,) conducted a other in Cognitive dysfunction. Selective HCN1 inhibitors vs. Prior non-selective HCN antagonists was evaluated on Working memory recovery and cardiac physiology. Selective HCN1 inhibitors enhanced excitatory postsynaptic potential summation and recovered working memory in rats without altering cardiac physiology.