High throughput quantitative pharmacology: cross platform comparison of ion channel activating compounds for pain


F Gaffey1; D McCoull1; S Bourne1; J M Large1; J Jerman1; P D Wright1
1 LifeArc, UK


Ion channels represent an attractive group of proteins for therapeutic intervention. Recent screening advances have facilitated previously unachievable large scale pharmacological investigation of this protein class, alongside detailed dissection of published tool molecules. The two-pore domain potassium (K2P) family of ion channels represent an interesting development opportunity for novel pain therapeutic development and fundamental research.

Primarily acting as ‘leak channels’ for potassium ions, the K2Ps are crucial for maintaining resting membrane potential in excitable and non-excitable mammalian cells. Dysfunction is highly associated with improper somatosensory activity, manifesting in numerous and varied pain phenotypes. Expression patterns, disease linkage studies and genetic evidence implicate the K2P channels TREK-2 and TREK-1 in these phenotypes; channel knock out facilitates increased spontaneous pain or increased sensitivity to mechanical and thermal pain, respectively. 

To date, no K2P channel activators exist for treatment of pain conditions. Given current therapies are greatly limited by incomplete efficacy, addictive properties and/or sedation, there is an urgent need for new analgesics. However, there has been a paucity of well described pharmacological tools with which to probe the precise function of TREK channels and facilitate drug discovery. 

Here, we investigate the pharmacology of published tool activator compounds against TREK-2 and TREK-1, providing a comparative resource to the K2P research community, aiding novel therapeutic development. Using a high throughput thallium flux system, alongside manual and automated patch clamp electrophysiology, we examine the robustness and reproducibility of multiple tool compounds, comparing K2P activation within and across systems. We demonstrate which tool compounds are most potent and those which do not perform consistently over multiple assay platforms.

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