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.
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.
Tertyshnikova
Svetlana
S
Neuroscience Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Neuroscience Drug Discovery, 5 Research Parkway, Wallingford, CT 06492-7660, USA. svetlana.tertyshnikova@bms.com
Knox
Ronald J
RJ
Plym
Mary Jane
MJ
Thalody
George
G
Griffin
Corinne
C
Neelands
Torben
T
Harden
David G
DG
Signor
Laura
L
Weaver
David
D
Myers
Robert A
RA
Lodge
Nicholas J
NJ
D000758:Anesthesia; D000818:Animals; D001464:Barium / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000819:agonists*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013777:Tetrazoles / Q000494:pharmacology*; D001743:Urinary Bladder / Q000187:drug effects*
C500526:(5,6,7,8-tetrahydronaphthalen-1-yl)-(2-(1H-tetrazol-5-yl)phenyl)amine; D015221:Potassium Channels; D013764:Tetrahydronaphthalenes; D013777:Tetrazoles; D001464:Barium