BL 1249

[(5, 6, 7, 8-tetrahydro-naphthalen-1-yl)-[2-(1H-tetrazol-5-yl)-phenyl]-amine], named BL 1249, is a putative potassium channel opener with bladder-relaxant properties. In cultured bladder smooth muscle cells, BL 1249 decreased DiBAC4 (3) fluorescence in a concentration-dependent manner with an EC50 of 1.26 ± 0.6 µM. In human bladder cells, BL 1249 resulted in hyperpolarization in a concentration-dependent manner and yielded an EC50 of 1.49±0.08 µM. BL 1249 relaxed 30 mM KCl precontracted bladder strips in a concentration-dependent manner and yielded an EC50 of 1.1 ± 0.37 µM [1].

There are several types of potassium channels in urinary bladder myocytes and they are important in determining contractility and excitability of bladder smooth muscle. These channels include maxi-K+, KATP, members of the voltage-gated Kv family, SK family and, possibly, members of the KCNQ family. Open potassium channels can increase potassium efflux from the cell and produce membrane potential hyperpolarization, thereby decrease the activation of voltage-dependent calcium channels [1].

In human bladder myocytes, BL 1249 produced large instantaneously non-inactivating, activating outward currents that were readily reversible following drug washout. The BL 1249-induced current was hence of a reversal potential of near -80 mV under the physiological K+ gradient, this indicated that the current is carried by K+ ions [1].

In anesthetized rats, BL 1249 at a concentration of 1 mg/kg significantly decreased (p< 0.01) micturition contractions during the 15-min period immediately following dosing; for the 15- to 30-min period, the decrease was significant but less (p< 0.05). Administration of BL 1249 at a concentration of 1 mg/kg had no effect on mean arterial blood pressure (MABP) during the 0- to 15-min period immediately following administration. During the 15- to 30-min period, BL 1249 administration increased MABP by less than 10% [1].

Reference:
[1].  Svetlana Tertyshnikova, Ronald J. Knox, Mary Jane Plym, et al. BL-1249 [(5, 6, 7, 8-Tetrahydro-naphthalen-1-yl)-[2-(1H-tetrazol-5-yl)-phenyl]-amine]: A Putative Potassium Channel Opener with Bladder-Relaxant Properties. The Journal of Pharmacology and Experimental Therapeutics, 2015, 313(1):250-259.

BL-1249 [(5,6,7,8-tetrahydro-naphthalen-1-yl)-[2-(1H-tetrazol-5-yl)-phenyl]-amine]: a putative potassium channel opener with bladder-relaxant properties.[Pubmed:15608074]

J Pharmacol Exp Ther. 2005 Apr;313(1):250-9.

BL-1249 [(5,6,7,8-tetrahydro-naphthalen-1-yl)-[2-(1H-tetrazol-5-yl)-phenyl]-amine] produced 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 = 1.26 +/- 0.6 microM) or by direct electrophysiological measurement (EC50 = 1.49 +/- 0.08 microM). BL-1249 also produced a membrane hyperpolarization of acutely dissociated rat bladder myocytes. Voltage-clamp studies in human bladder cells revealed that BL-1249 activated an instantaneous, noninactivating current that reversed near E(K). The BL-1249-evoked outward K+ current was insensitive to blockade by glyburide, tetraethylammonium, iberiotoxin, 4-aminopyridine, apamin, or Mg2+. However, the current was inhibited by extracellular Ba2+ (10 mM). In in vitro organ bath experiments, BL-1249 produced a concentration-dependent relaxation of 30 mM KCl-induced contractions in rat bladder strips (EC50 = 1.12 +/- 0.37 microM), yet had no effect on aortic strips up to the highest concentration tested (10 microM). The bladder relaxation produced by BL-1249 was partially blocked by Ba2+ (1 and 10 mM) but not by apamin, iberiotoxin, 4-aminopyridine, glyburide, or tetraethylammonium. In an anesthetized rat model, BL-1249 (1 mg/kg i.v.) decreased the number of isovolumic contractions, without significantly affecting blood pressure. Thus, BL-1249 behaves as a potassium channel activator that exhibits bladder versus vascular selectivity both in vitro and in vivo. A survey of potassium channels exhibiting sensitivity to extracellular Ba2+ at millimolar concentration revealed that the expression of the K2P2.1 (TREK-1) channel was relatively high in human bladder cells versus human aortic cells, suggesting this channel as a possible candidate target for BL-1249.

Investigation of the role of TASK-2 channels in rat pulmonary arteries; pharmacological and functional studies following RNA interference procedures.[Pubmed:16432512]

Br J Pharmacol. 2006 Mar;147(5):496-505.

In the present study, we investigated the ability of RNA interference technology to suppress TASK-2 potassium channel expression in human embryonic kidney (HEK293) cells stably transfected with TASK-2 cDNA and in rat isolated intact pulmonary arteries. Lipofectamine-induced transfection of a specific siRNA sequence targeted against TASK-2 resulted in a dose- and time-dependent decrease in TASK-2 channel protein expression. In siRNA-transfected cells the TASK-2 peak currents were significantly smaller than in control cells at every investigated pH, while the pH sensitivity was not altered. Using scrambled siRNA as a negative control, there were no significant changes in TASK-2 protein expression or current compared to mock-transfected cells. In TASK-2 siRNA-transfected small pulmonary arteries, but not in scrambled siRNA-treated vessels, myocyte resting membrane potential at pH 7.4 was significantly less negative and the hyperpolarisations in response to increasing pH from 6.4 to 8.4 were significantly smaller compared with control. The application of levcromakalim (10 microM), NS1619 (33 microM) and a potassium channel inhibitor cocktail (5 mM 4-aminopyridine, 10 mM tetraethylammonium chloride, 30 microM Ba2+ and 10 microM glibenclamide) had similar effects in control and in siRNA-transfected vessels. The TASK-1 (anandamide-sensitive) contribution to resting membrane potential was comparable in each group. Clofilium (100 microM) generated significantly smaller responses in transfected artery segments. These results suggest that RNA interference techniques are effective at inhibiting TASK-2 channel expression in cultured cells and in intact vessels and that TASK-2 channels have a functional role in setting the membrane potential of pulmonary artery myocytes.

BL-1249 is a nonsteroidal anti-inflammatory drug (NSAID) and a potassium channel activator. 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. BL-1249 extracellular application activates all TREK subfamily members but has no effect on other K2P subfamilies. BL-1249 exhibits more selective for the bladder (EC50 of 1.26 μM) than vascular tissue (EC50 of 21.0 μM).

BL 1249,18200-13-0,Natural Products,Potassium Channel, buy BL 1249 , BL 1249 supplier , purchase BL 1249 , BL 1249 cost , BL 1249 manufacturer , order BL 1249 , high purity BL 1249