Selective KCNH2-3.1 Inhibitors for the Treatment of Schizophrenia and Other CNS Disorders

This technology includes compounds, pharmaceutical compositions and methods of treating or preventing neurological or psychiatric disorders for which inhibiting KCNH2-3.1 containing potassium channels provides a therapeutic effect. Polymorphisms in the KCNH2 gene have been associated with altered cognitive function and schizophrenia. The KCNH2 gene encodes the protein which forms the human ether-a-go-go related (hERG) voltage-gated potassium channel 4, 5. The risk-associated alleles predict impaired cognitive function in both patients and healthy controls as well as overexpression of KCNH2-3.1, a truncated isoform with unique electrophysiological properties. KCNH2-3.1 is a primate-specific isoform, enriched in the brain, which lacks the PAS domain critical for the slow-deactivation properties of hERG channels. ERG channels have been shown to regulate the activity of neurons in multiple brain regions, suggesting a possible cause of the cognitive dysfunction in patients with schizophrenia associated with elevated KCNH2-3.1 may be decreased synchrony among functionally connected neurons. Those with overexpression of KCNH2-3.1 exhibit more inefficient neuronal processing in the hippocampus and frontal cortex during memory tasks as measured with fMRI1.