Abstract

There is currently a high unmet need for the identification of novel treatments for chronic pain. Current treatments are characterized by their lack of efficacy in a large proportion of patients and greatly limiting side effects. A growing body of evidence, including human genetic association, has linked two-pore domain potassium (K2P) channels to the regulation of multiple types of pain. Despite this there are no current therapies which target K2P channels. One reason for this is the lack of pharmacological tools by which to probe channel function and therapeutic utility. We sought to develop a high-throughput system to rapidly and efficiently identify activators of K2P channels. We have shown that the identification of ion channel activators can be compromised when the target is expressed at high levels. To avoid this, we developed cellular systems designed and optimized for the identification of channel activators. This was used to screen a LifeArc compound set across the K2P superfamily. Novel and selective activators were identified, and activity confirmed for a subset using electrophysiology. This work identified K2P drug targets which are amenable to small molecule activation, de-risking multiple channels from a technical point of view and provided selective starting points for future optimization.