Discovery of a Pharmacologically Active Antagonist of the Two‐Pore‐Domain Potassium Channel K_2P9.1 (TASK‐3)

Abstract

TWIK-related acid-sensitive K(+) (K(2P) 9.1, TASK-3) ion channels have the capacity to regulate the activity of neuronal pathways by influencing the resting membrane potential of neurons on which they are expressed. The central nervous system (CNS) expression of these channels suggests potential roles in neurologic disorders, and it is believed that the development of TASK-3 antagonists could lead to the therapeutic treatment of a number of neurological conditions. While a therapeutic potential for TASK-3 channel modulation exists, there are only a few documented examples of potent and selective small-molecule channel blockers. Herein, we describe the discovery and lead optimization efforts for a novel series of TASK-3 channel antagonists based on a 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine high-throughput screening lead from which a subseries of potent and selective inhibitors were identified. One compound was profiled in detail with respect to its physical properties and demonstrated pharmacological target engagement as indicated by its ability to modulate sleep architecture in rodent electroencephalogram (EEG) telemetry models.

Ion Channel Profile of TRPM8 Cold Receptors Reveals a Role of TASK-3 Potassium Channels in Thermosensation

“…Recently, a specific inhibitor, a 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine analog, was described for recombinant human TASK-3 channels, with a 10-fold potency over TASK-1 (Coburn et al, 2012). We tested the effect of this drug, known as compound 23 (C23), on mouse TASK-3 channels overexpressed in HEK293 cells.…”

Breathing Stimulant Compounds Inhibit TASK-3 Potassium Channel Function Likely by Binding at a Common Site in the Channel Pore

“…PKTHPP and A1899 were custom synthesized by Aberjona Laboratories (Beverly, MA) and Dr. Brijesh Bhayana (Massachusetts General Hospital Department of Dermatology), respectively, using published methods (Peukert et al, 2003;Coburn et al, 2012). PKTHPP and A1899 were solubilized in dimethylsulfoxide (DMSO; 10 mM stock); N-ethylmaleimide (NEM) was solubilized in DMSO (1 M stock).…”

“…A number of selective, high-potency TASK-blocking compounds have been identified, and some are in clinical use or have undergone preclinical studies (Putzke et al, 2007;Brendel et al, 2009;Streit et al, 2011;Coburn et al, 2012;Flaherty et al, 2014). Doxapram is a breathing stimulant and carotid body-activating drug developed in the 1960s for use in human and veterinary medicine (Lunsford et al, 1964).…”

Functional TASK-3–Like Channels in Mitochondria of Aldosterone-Producing Zona Glomerulosa Cells

“…To establish if TASK-3 is functionally active on H295R cell plasma membranes, we used a novel TASK-3 antagonist compound C23 (C23) modeled on 5,6,7,8-tetrahydropyrido[4,3- d ]pyrimidine 34 . C23 shows good selectivity for TASK-3 over other two-pore domain K + channels, and a potency of 35 nM (IC 50 for current inhibition) 34 .…”