Identification of potent and highly selective chiral tri-amine and tetra-amine μ opioid receptors ligands: An example of lead optimization using mixture-based libraries

The generation of chiral polyamine libraries has been successfully accomplished in our laboratory following exhaustive reduction of resin-bound peptides. Herein, we report the synthesis and screening results of a positional scanning mixture-based library of chiral hepta-amines in a radioreceptor assay for the opioid receptor. The positional scanning hepta-amine library was generated by the exhaustive reduction of a library of 34,012,070 hexapeptides. Following screening of the entire library, combinations of the most active functionalities found at each position were used to synthesize and screen 40 individual hepta-amines and served as starting ‘hits’ for further SAR studies. The individual compounds showed IC50 values ranging from 14 to 345 nM. As might be anticipated by the known studies of μ opiate antagonists, the identified active hepta-amines possessed aromatic rings derived from phenylalanine and tyrosine amino acid side chains. Following SAR studies, a truncation analog, reduced and permethylated YYF-NH2, was found to be highly active (0.5 nM) as a selective μ antagonist in the guinea pig ileum bioassay.

Screening of a mixture based heptaamine library (34,012,170 compounds) against μ opioid receptor and identification of highly active heptaamine compounds.Figure optionsDownload as PowerPoint slide