Discovery of nanomolar ligands for 7-transmembrane G-protein-coupled receptors from a diverse N-(substituted)glycine peptoid library

J Med Chem. 1994 Aug 19;37(17):2678-85. doi: 10.1021/jm00043a007.

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.

Publication types

  • Comparative Study

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding, Competitive
  • Brain / metabolism
  • Databases, Factual
  • Dipeptides / metabolism*
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Enkephalins / metabolism
  • GTP-Binding Proteins / metabolism*
  • Glycine / analogs & derivatives*
  • Glycine / metabolism*
  • Ligands
  • Molecular Sequence Data
  • Molecular Structure
  • Oligopeptides / metabolism*
  • Peptoids
  • Prazosin / metabolism
  • Radioligand Assay
  • Rats
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Receptors, Cell Surface / metabolism*
  • Receptors, Opioid, mu / metabolism
  • Structure-Activity Relationship

Substances

  • Dipeptides
  • Enkephalins
  • Ligands
  • Oligopeptides
  • Peptoids
  • Receptors, Adrenergic, alpha-1
  • Receptors, Cell Surface
  • Receptors, Opioid, mu
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • CHIR 2279
  • CHIR 4531
  • GTP-Binding Proteins
  • Glycine
  • Prazosin