Discovery of Nanomolar Ligands for 7-Transmembrane G-Protein-Coupled Receptors from a Diverse N-(Substituted)glycine Peptoid Library

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1994-08, Vol.37 (17), p.2678-2685
Main Authors: Zuckermann, Ronald N, Martin, Eric J, Spellmeyer, David C, Stauber, Gregory B, Shoemaker, Kevin R, Kerr, Janice M, Figliozzi, Gianine M, Goff, Dane A, Siani, Michael A, Simon, Reyna J, Banville, Steven C, Brown, Edward G, Wang, Liang, Richter, Lutz S, Moos, Walter H
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Binding, Competitive
Biological and medical sciences
Brain - metabolism
Databases, Factual
Dipeptides - metabolism
Enkephalin, Ala-MePhe-Gly
Enkephalins - metabolism
Glycine - analogs & derivatives
Glycine - metabolism
GTP-Binding Proteins - metabolism
Ligands
Medical sciences
Miscellaneous
Molecular Sequence Data
Molecular Structure
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Oligopeptides - metabolism
Peptoids
Pharmacology. Drug treatments
Prazosin - metabolism
Radioligand Assay
Rats
Receptors, Adrenergic, alpha-1 - metabolism
Receptors, Cell Surface - metabolism
Receptors, Opioid, mu - metabolism
Structure-Activity Relationship
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Description
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00043a007