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 ''peptoids'' 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 sidechains was biased to resemble known ligands to 7-transmembrane G-protein coupled receptors. All peptoids were screened in solution-phase, competitive radioligand binding assays. Peptoid trimer CHIR 2279 binds to the alpha(1)-adrenergic receptor with a K-i of 5 nM, and trimer CHIR 4531 binds to the mu-opiate receptor with a K-i of 6 nM. This represents the first example of the discovery of high-affinity receptor ligands Aom a combinatorial library of non-natural chemical entities.