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

Area of Science:

• Neuroscience
• Pharmacology
• Ion Channel Biology

Background:

• Hyperpolarization-activated and cyclic-nucleotide-gated 1 (HCN1) channels are implicated in cognitive functions.
• Existing HCN1 antagonists lack selectivity, potency, and in vivo efficacy, hindering research and therapeutic development.

Purpose of the Study:

• To identify and characterize potent and selective inhibitors of HCN1 channels.
• To investigate the physiological effects of selective HCN1 inhibition in neural circuits and cognitive behavior.
• To assess the safety profile of selective HCN1 inhibitors, particularly concerning cardiac function.

Main Methods:

• Automated electrophysiology screening of a small-molecule library.
• Chemical optimization to develop a primary carboxamide series of HCN1 inhibitors.
• Electrophysiological recordings in cognition-relevant brain circuits.
• Behavioral testing (working memory) in rats.
• Assessment of cardiac function in human atrial cardiomyocytes and rats.

Main Results:

• Identification of a potent and selective HCN1 inhibitor series with a novel mode of action.
• Selective HCN1 inhibition enhanced excitatory postsynaptic potential summation in neural circuits.
• Administration of selective HCN1 inhibitors restored working memory deficits in rats.
• Selective HCN1 inhibition showed no adverse effects on cardiac physiology in vitro or in vivo.

Conclusions:

• Selective HCN1 inhibitors effectively target HCN1 channels in the brain.
• HCN1 inhibition shows therapeutic potential for treating cognitive dysfunction.
• Selective HCN1 inhibitors offer a safer alternative to non-selective antagonists for neurological disorders.