Unpredictable stereochemical preferences for mu opioid receptor activity in an exhaustively stereodiversified library of 1,4-enediols.
Using olefin cross-metathesis, we synthesized a novel stereodiversified library of compounds 3 containing a trans-1,4-enediol. Screening this library for mu opioid receptor (MOR) affinity identified multiple high-affinity ligands and revealed that the stereochemical configuration varied widely among those ligands having the highest affinity. It was not possible to predict the configurations of the most active compounds 3 on the basis of the configuration of endomorphin-2, a known MOR peptide ligand, validating the diversity-based approach to ligand discovery.
Shi
Zhangjie
Z
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Harrison
Bryce A
BA
Verdine
Gregory L
GL
D000438:Alcohols / Q000737:chemistry* / Q000378:metabolism*; D000475:Alkenes / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D020650:Combinatorial Chemistry Techniques; D006224:Cricetinae; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D013379:Substrate Specificity; D013462:Sulfur Radioisotopes
D000438:Alcohols; D000475:Alkenes; D017450:Receptors, Opioid, mu; D013462:Sulfur Radioisotopes; D016244:Guanosine 5'-O-(3-Thiotriphosphate)