Abstract
Following interrogation of a wide-ligand profile database, a nonselective norepinephrin reuptake inhibitor was converted into a novel muscarinic antagonist using two medicinal chemistry transformations (M3/NRI selectivity of >1000). Conjugation to a β(2) agonist motif furnished a molecule with balanced dual pharmacology, as demonstrated in a guinea pig trachea tissue model of bronchoconstriction. This approach provides new starting points for the treatment of chronic obstructive pulmonary disease and illustrates the potential for building selectivity into GPCR modulators that possess intrinsic promiscuity or reverse selectivity.
MeSH terms
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Adrenergic Uptake Inhibitors / chemical synthesis*
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Adrenergic Uptake Inhibitors / chemistry
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Adrenergic Uptake Inhibitors / pharmacology
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Adrenergic beta-2 Receptor Agonists / chemical synthesis*
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Adrenergic beta-2 Receptor Agonists / chemistry
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Adrenergic beta-2 Receptor Agonists / pharmacology
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Animals
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Bronchoconstriction / drug effects
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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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Caco-2 Cells
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Cell Membrane Permeability
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Guinea Pigs
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Humans
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In Vitro Techniques
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Microsomes, Liver / metabolism
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Models, Molecular
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Muscarinic Antagonists / chemical synthesis*
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Muscarinic Antagonists / chemistry
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Muscarinic Antagonists / pharmacology
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Pulmonary Disease, Chronic Obstructive / drug therapy*
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Receptor, Muscarinic M3 / physiology*
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Structure-Activity Relationship
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Trachea / drug effects
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Trachea / physiopathology
Substances
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Adrenergic Uptake Inhibitors
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Adrenergic beta-2 Receptor Agonists
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Bronchodilator Agents
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Muscarinic Antagonists
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Receptor, Muscarinic M3