Abstract
We have discovered a novel series of N-[2-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-naphthalen-1-yl] amides that are potent openers of K(ATP) channels and investigated structure-activity relationships (SAR) around the 1,2-disubstituted naphthyl core. A-151892, a prototype compound of this series, was found to be a potent and efficacious potassium channel opener in vitro in transfected Kir6.2/SUR2B cells and pig bladder strips. Additionally, A-151892 was found to selectively inhibit unstable bladder contractions in vivo in an obstructed rat model of myogenic bladder function
MeSH terms
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ATP-Binding Cassette Transporters / agonists
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ATP-Binding Cassette Transporters / genetics
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Amides / administration & dosage
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Amides / chemical synthesis*
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Amides / pharmacology*
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Animals
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Blood Pressure / drug effects
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Cell Line
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Fluorescent Dyes
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Humans
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Hypertrophy / drug therapy
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Male
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Membrane Potentials / drug effects
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Muscle Contraction / drug effects
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Naphthalenes / administration & dosage
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Naphthalenes / chemical synthesis
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Naphthalenes / pharmacology
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Potassium Channels / agonists*
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Potassium Channels / genetics
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Potassium Channels, Inwardly Rectifying / agonists
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Potassium Channels, Inwardly Rectifying / genetics
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Rats
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Rats, Sprague-Dawley
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Receptors, Drug / agonists
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Receptors, Drug / genetics
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Structure-Activity Relationship
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Sulfonylurea Receptors
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Swine
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Transfection
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Urinary Bladder / pathology
Substances
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ATP-Binding Cassette Transporters
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Amides
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Fluorescent Dyes
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Naphthalenes
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Potassium Channels
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Potassium Channels, Inwardly Rectifying
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Receptors, Drug
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Sulfonylurea Receptors