BL-1249 is a nonsteroidal anti-inflammatory drug (NSAID) and a potassium channel activator. BL-1249 potently activates K_2P2.1 (TREK-1) and K_2P10.1 (TREK-2) with EC₅₀ values of 5.5 μM and 8.0 μM, respectively. BL-1249 extracellular application activates all TREK subfamily members but has no effect on other K_2P subfamilies. BL-1249 exhibits more selective for the bladder (EC₅₀ of 1.26 μM) than vascular tissue (EC₅₀ of 21.0 μM)^[1][2]. IC50 & Target: EC50: 5.5 μM (TREK-1) and 8.0 μM (TREK-2)^[1] In Vitro: BL-1249 produces a concentration-dependent membrane hyperpolarization of cultured human bladder myocytes, assessed as either a reduction in fluorescence of the voltage-sensitive dye bis-(1,2-dibutylbarbituric acid)trimethine oxonol (EC₅₀ of 1.26 μM) or by direct electrophysiological measurement EC₅₀ of 1.49 μM). BL-1249 produced a concentration-dependent hyperpolarization with an EC₅₀ of 21.0 μM in human aortic smooth muscle cells^[1].
In 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), yet has no effect on aortic strips up to the highest concentration tested (10 μM). The bladder relaxation produced by BL-1249 is partially blocked by Ba²⁺ (1 and 10 mM)^[1].
BL-1249 is a selective agonist of the TREK subfamily when applied extracellularly, having preferential action on K_2P2.1(TREK-1) and K_2P10.1(TREK-2) over K_2P4.1(TRAAK) and establish that its mechanism of action relies on gating at the selectivity filter C-type gate^[2]. In Vivo: BL-1249 (1 mg/kg) inhibits isovolumic bladder contractions in vivo. The short duration of the effect of BL-1249 on bladder contraction ( 30 min) is likely due to a fast elimination half-life of the compound after i.v. administration (0.69 h)^[1].
BL-1249 (1 mg/kg) has little effect on mean arterial blood pressure, an observation again consistent with the in vitro bladder to vascular relaxant selectivity^[1].