Abstract
Structure-activity relationships were investigated on a novel series of tricyclic dihydropyridine-containing K(ATP) openers. This diverse group of analogues, comprising a variety of heterocyclic rings fused to the dihydropyridine nucleus, was designed to determine the influence on activity of hydrogen-bond-donating and -accepting groups and their stereochemical disposition. Compounds were evaluated for K(ATP) activity in guinea pig bladder cells using a fluorescence-based membrane potential assay and in a pig bladder strip assay. The inhibition of spontaneous bladder contractions in vitro was also examined for a subset of compounds. All compounds studied showed greater potency to inhibit spontaneous bladder contractions relative to their potencies to inhibit contractions elicited by electrical stimulation.
MeSH terms
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Adenosine Triphosphate / physiology*
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Animals
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Dihydropyridines / chemical synthesis*
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Dihydropyridines / chemistry
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Dihydropyridines / pharmacology
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Electric Stimulation
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Guinea Pigs
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Hemodynamics / drug effects
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Heterocyclic Compounds, 3-Ring / chemical synthesis*
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Heterocyclic Compounds, 3-Ring / chemistry
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Heterocyclic Compounds, 3-Ring / pharmacology
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Hydrogen Bonding
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In Vitro Techniques
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Membrane Potentials
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Muscle Contraction / drug effects
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Muscle, Smooth / cytology
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Muscle, Smooth / drug effects
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Muscle, Smooth / physiology
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Potassium Channels / drug effects*
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Stereoisomerism
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Structure-Activity Relationship
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Swine
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Urinary Bladder / cytology
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Urinary Bladder / drug effects*
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Urinary Bladder / physiology
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Urodynamics / drug effects
Substances
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Dihydropyridines
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Heterocyclic Compounds, 3-Ring
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Potassium Channels
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Adenosine Triphosphate