In vitro and in vivo characterization of a novel naphthylamide ATP‐sensitive K+ channel opener, A‐151892

Openers of ATP‐sensitive K+ channels are of interest in several therapeutic indications including overactive bladder and other lower urinary tract disorders. This study reports on the in vitro and in vivo characterization of a structurally novel naphthylamide N‐[2‐(2,2,2‐trifluoro‐1‐hydroxy‐1‐triflu...

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Published in:British journal of pharmacology 2004-09, Vol.143 (1), p.81-90
Main Authors: Gopalakrishnan, Murali, Buckner, Steven A, Shieh, Char‐Chang, Fey, Thomas, Fabiyi, Adebola, Whiteaker, Kristi L, Davis‐Taber, Rachel, Milicic, Ivan, Daza, Anthony V, Scott, Victoria E S, Castle, Neil A, Printzenhoff, David, London, Brecht, Turner, Sean C, Carroll, William A, Sullivan, James P, Coghlan, Michael J, Brune, Michael E
Format: Article
Language:English
Subjects:
Acetamides - pharmacology
Adenosine Triphosphate - physiology
Animals
ATP‐sensitive K+ channel
A‐151892
Barbiturates - metabolism
Binding, Competitive - drug effects
Biological and medical sciences
Blood Pressure - drug effects
Blood Vessels - drug effects
Female
glibenclamide
Guanidines - pharmacology
Guinea Pigs
In Vitro Techniques
Iodine Radioisotopes
Isoxazoles - metabolism
Medical sciences
Membrane Potentials - drug effects
Muscle Relaxation - drug effects
Muscle, Smooth, Vascular - drug effects
Naphthalenes - pharmacology
naphthylamides
overactive bladder
Patch-Clamp Techniques
Pharmacology. Drug treatments
potassium channel opener
Potassium Channels - agonists
Pyridines - pharmacology
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Swine
urinary bladder
Urinary Bladder - drug effects
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Summary:Openers of ATP‐sensitive K+ channels are of interest in several therapeutic indications including overactive bladder and other lower urinary tract disorders. This study reports on the in vitro and in vivo characterization of a structurally novel naphthylamide N‐[2‐(2,2,2‐trifluoro‐1‐hydroxy‐1‐trifluoromethyl‐ethyl)‐naphthalen‐1‐yl]‐acetamide (A‐151892), as an opener of the ATP‐sensitive potassium channels. A‐151892 was found to be a potent and efficacious potassium channel opener (KCO) as assessed by glibenclamide‐sensitive whole‐cell current and fluorescence‐based membrane potential responses (−log EC50=7.63) in guinea‐pig bladder smooth muscle cells. Evidence for direct interaction with KCO binding sites was derived from displacement of binding of the 1,4‐dihydropyridine opener [125I]A‐312110. A‐151892 displaced [125I]A‐312110 binding to bladder membranes with a −log Ki value of 7.45, but lacked affinity against over 70 neurotransmitter receptor and ion channel binding sites. In pig bladder strips, A‐151892 suppressed phasic, carbachol‐evoked and electrical field stimulus‐evoked contractility in a glibenclamide‐reversible manner with −log IC50 values of 8.07, 7.33 and 7.02 respectively, comparable to that of the potencies of the prototypical cyanoguanidine KCO, P1075. The potencies to suppress contractions in thoracic aorta (−log IC50=7.81) and portal vein (−log IC50=7.98) were not substantially different from those observed for suppression of phasic contractility of the bladder smooth muscle. In vivo, A‐151892 was found to potently suppress unstable bladder contractions in obstructed models of unstable contractions in both pigs and rats with pED35% values of 8.05 and 7.43, respectively. These results demonstrate that naphthylamide analogs exemplified by A‐151892 are novel KATP channel openers and may serve as chemotypes to exploit additional analogs with potential for the treatment of overactive bladder and lower urinary tract symptoms. British Journal of Pharmacology (2004) 143, 81–90. doi:10.1038/sj.bjp.0705908
ISSN:0007-1188
1476-5381
DOI:10.1038/sj.bjp.0705908