In vitro and in vivo characterization of a novel naphthylamide ATP-sensitive K+ channel opener, A-151892.
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.
Gopalakrishnan
Murali
M
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. mural.gopalakrishnan@abbott.com
Buckner
Steven A
SA
Shieh
Char-Chang
CC
Fey
Thomas
T
Fabiyi
Adebola
A
Whiteaker
Kristi L
KL
Davis-Taber
Rachel
R
Milicic
Ivan
I
Daza
Anthony V
AV
Scott
Victoria E S
VE
Castle
Neil A
NA
Printzenhoff
David
D
London
Brecht
B
Turner
Sean C
SC
Carroll
William A
WA
Sullivan
James P
JP
Coghlan
Michael J
MJ
Brune
Michael E
ME
D000081:Acetamides / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D001463:Barbiturates / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D007555:Isoxazoles / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000819:agonists*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013552:Swine; D001743:Urinary Bladder / Q000187:drug effects
C496065:A-151892; D000081:Acetamides; D001463:Barbiturates; D006146:Guanidines; D007457:Iodine Radioisotopes; D007555:Isoxazoles; D009281:Naphthalenes; D015221:Potassium Channels; D011725:Pyridines; C052795:bis(1,3-dibutylbarbiturate)trimethine oxonol; C073896:N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine; D000255:Adenosine Triphosphate