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In vitro and in vivo characterization of a novel naphthylamide ATP‐sensitive K + channel opener, A‐151892
Author(s) -
Gopalakrishnan Murali,
Buckner Steven A,
Shieh CharChang,
Fey Thomas,
Fabiyi Adebola,
Whiteaker Kristi L,
DavisTaber 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
Publication year - 2004
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705908
Subject(s) - chemistry , potassium channel opener , overactive bladder , carbachol , in vivo , glibenclamide , potassium channel , contractility , agonist , pharmacology , endocrinology , medicine , receptor , biophysics , biochemistry , biology , pathology , microbiology and biotechnology , alternative medicine , diabetes mellitus
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 EC 50 =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 [ 125 I]A‐312110. A‐151892 displaced [ 125 I]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 IC 50 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 IC 50 =7.81) and portal vein (−log IC 50 =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 pED 35% values of 8.05 and 7.43, respectively. These results demonstrate that naphthylamide analogs exemplified by A‐151892 are novel K ATP 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