Abstract
Screening a diverse, combinatorial library of ca. 5000 synthetic dimer and trimer N-(substituted)glycine "peptides" yielded novel, high-affinity ligands for 7-transmembrane G-protein-coupled receptors. The peptoid library was efficiently assembled using readily available chemical building blocks. The choice of side chains was biased to resemble known ligands to 7-transmembrane G-protein-coupled receptors. All peptides were screened in solution-phase, competitive radioligand-binding assays. Peptoid trimer CHIR 2279 binds to the alpha 1-adrenergic receptor with a Ki of 5 nM, and trimer CHIR 4531 binds to the mu-opiate receptor with a Ki of 6 nM. This represents the first example of the discovery of high-affinity receptor ligands from a combinatorial library of non-natural chemical entities.
MeSH terms
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Amino Acid Sequence
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Animals
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Binding, Competitive
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Brain / metabolism
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Databases, Factual
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Dipeptides / metabolism*
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Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
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Enkephalins / metabolism
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GTP-Binding Proteins / metabolism*
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Glycine / analogs & derivatives*
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Glycine / metabolism*
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Ligands
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Molecular Sequence Data
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Molecular Structure
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Oligopeptides / metabolism*
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Peptoids
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Prazosin / metabolism
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Radioligand Assay
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Rats
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Receptors, Adrenergic, alpha-1 / metabolism
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Receptors, Cell Surface / metabolism*
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Receptors, Opioid, mu / metabolism
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Structure-Activity Relationship
Substances
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Dipeptides
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Enkephalins
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Ligands
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Oligopeptides
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Peptoids
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Receptors, Adrenergic, alpha-1
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Receptors, Cell Surface
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Receptors, Opioid, mu
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Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
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CHIR 2279
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CHIR 4531
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GTP-Binding Proteins
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Glycine
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Prazosin