Abstract
To discover a highly selective M(3) antagonist, a combinatorial library was prepared. The library was designed to identify a novel structural class of M(3) antagonists by exploring the spatial arrangement of the pharmacophores in known M(3) antagonists. After the evaluation of 1000 library members, a potent M(3) antagonist, 14a (K(i) = 0.31 nM), with novel structural features was identified. Compound 14a showed high selectivity for M(3) receptors over the other muscarinic receptor subtypes (M(1)/M(3) = 380-fold, M(2)/M(3) = 98-fold, M(4)/M(3) = 45-fold, M(5)/M(3) = 120-fold).
MeSH terms
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Acetylcholine
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Animals
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Bradycardia / chemically induced
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Bradycardia / physiopathology
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Bronchoconstriction / drug effects
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CHO Cells
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Carbachol
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Cholinergic Agents
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Combinatorial Chemistry Techniques
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Cricetinae
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Dipeptides / chemical synthesis*
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Dipeptides / chemistry
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Dipeptides / pharmacology
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Heart Atria / drug effects
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Humans
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In Vitro Techniques
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Muscarinic Antagonists / chemical synthesis*
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Muscarinic Antagonists / chemistry
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Muscarinic Antagonists / metabolism
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / metabolism
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Piperidines / pharmacology
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Rats
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Receptor, Muscarinic M3
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Receptors, Muscarinic / drug effects*
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Receptors, Muscarinic / metabolism
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Structure-Activity Relationship
Substances
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Cholinergic Agents
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Dipeptides
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Muscarinic Antagonists
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N-(2-(3-((1-(cyclohexylmethyl)-3-piperidinyl)methylamino)-3-oxopropyl)amino-2-oxoethyl)-3,3,3-triphenylpropionamide
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Piperidines
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Receptor, Muscarinic M3
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Receptors, Muscarinic
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Carbachol
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Acetylcholine