BL-1249, a NSAID, is a Selective and Dual TREK-1 and TREK-2 Activator

K2P (KCNK) potassium channels belong to the voltage-gated ion channel (VGIC) superfamily. K2P channels can generate leak currents and stabilize the resting membrane potential of excitable cells. In addition, these channels link to various physiological and pathological processes including pain, anesthetic responses, arrhythmia, depression, and migraine. Therefore, the KCNK potassium channels is an attractive target for small molecule modulator to research.

BL-1249 is a nonsteroidal anti-inflammatory drug (NSAID) and a potassium channel K2P2.1(TREK-1) and TREK-2 activator.

In this article, we will precisely describe BL-1249 activity in vitro and in vivo.

Firstly, BL-1249 can produce a concentration-dependent membrane hyperpolarization. In human bladder myocyte cells, its application results in a reduction in fluorescence of voltage-sensitive dye bis-(1,2-dibutylbarbituric acid) trimethine oxonol, exhibits an EC50 of 1.26 μM. Electrophysiological measurement exhibits an EC50 of 1.49 μM. At the same time, BL-1249 produces a hyperpolarization (EC50 =21.0 μM) in human aortic smooth muscle cells.

Furthermore, in vitro organ bath experiments, BL-1249 produces a concentration-dependent relaxation of 30 mM KCl-induced contractions in rat bladder strips (EC50 of 1.12 μM). In contrast, it has no effect on aortic strips up to the highest concentration (10 μM).

BL-1249 is evaluated in an anesthetized rat model for its ability to alter isovolumic bladder contractions. Bladder contractions are recorded for 30 min post-treatment by separation into two 15-min periods for analysis.

Lastly, in an anesthetized rat model, BL-1249 (1 mg/kg; intravenous injection) relaxes 30 mM KCl precontracted-bladder strips in a concentration-dependent manner yielding an EC50 of 1.1 uM. But because of a fast elimination half-life of the compound, the duration of the effect of BL-1249 on bladder contraction (30 min) is short.

BL-1249 (1 mg/kg) has a little inhibitory effect on the rat aorta up to the highest concentration. This is an observation again consistent with the in vitro bladder to vascular relaxant selectivity.

In summary, the present article describes the activity of BL-1249, a putative potassium channel opener. BL-1249 potently activates K2P2.1 (TREK-1)and K2P10.1 (TREK-2) with EC50 values of 5.5 μM and 8.0 μM, respectively. In vivo, it is relatively selective for bladder versus vascular tissue. It exhibits more selective for the bladder (EC50 of 1.26 μM) than vascular tissue (EC50 of 21.0 μM).

Tertyshnikova S, et al. J Pharmacol Exp Ther. 2005 Apr;313(1):250-9.