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

Abstract：

:1. 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. 2. 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. 3. 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. 4. 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. 5. 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. 6. 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.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Gopalakrishnan M,Buckner SA,Shieh CC,Fey T,Fabiyi A,Whiteaker KL,Davis-Taber R,Milicic I,Daza AV,Scott VE,Castle NA,Printzenhoff D,London B,Turner SC,Carroll WA,Sullivan JP,Coghlan MJ,Brune ME

doi

10.1038/sj.bjp.0705908

subject

Has Abstract

pub_date

2004-09-01 00:00:00

pages

81-90

issue

eissn

0007-1188

issn

1476-5381

pii

sj.bjp.0705908

journal_volume

143

pub_type

杂志文章

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