Abstract
A series of novel biphenyl piperazines was discovered as highly potent muscarinic acetylcholine receptor antagonists via high throughput screening and subsequent optimization. Compound 5c with respective 500- and 20-fold subtype selectivity for M3 over M2 and M1 exhibited excellent inhibitory activity and long duration of action in a bronchoconstriction in vivo model in mice via intranasal administration. The novel inhaled mAChR antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease.
MeSH terms
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Administration, Intranasal
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Animals
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Bronchial Provocation Tests
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Bronchoconstriction / drug effects*
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Bronchoconstrictor Agents / pharmacology
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Bronchodilator Agents / chemical synthesis
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Bronchodilator Agents / chemistry
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Bronchodilator Agents / pharmacology*
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Disease Models, Animal
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Drug Evaluation, Preclinical
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Methacholine Chloride / pharmacology
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Mice
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Molecular Structure
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Piperazines / chemical synthesis
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Piperazines / chemistry
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Piperazines / pharmacology*
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Receptors, Muscarinic / drug effects*
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Bronchoconstrictor Agents
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Bronchodilator Agents
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Piperazines
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Receptors, Muscarinic
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Methacholine Chloride