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CELLULAR AND MOLECULAR

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

Neuroscience Drug Discovery (S.T., M.J.P., G.T., C.G., T.N., L.S., R.A.M., N.J.L.) and Lead Discovery and Profiling (R.J.K., D.G.H., D.W.), Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut

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 µM) or by direct electrophysiological measurement (EC₅₀ = 1.49 ± 0.08 µM). 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 µM), yet had no effect on aortic strips up to the highest concentration tested (10 µM). 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 K_2P2.1 (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.

Address correspondence to: Dr. Svetlana Tertyshnikova, Bristol-Myers Squibb Pharmaceutical Research Institute, Neuroscience Drug Discovery, 5 Research Parkway, Wallingford, CT 06492-7660. E-mail: svetlana.tertyshnikova{at}bms.com

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