Synthesis,biology, NMR and conformation studies of the topographically constrained δ‐opioid selective peptide analogs of [β‐iPrPhe3]deltorphin I |
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Authors: | S Liao M Shenderovich Z Zhang VJ Hruby KE Kvr K Hosohata P Davis F Porreca HI Yamamura |
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Institution: | S. Liao,M. Shenderovich,Z. Zhang,V.J. Hruby,K.E. Kövér,K. Hosohata,P. Davis,F. Porreca,H.I. Yamamura |
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Abstract: | Abstract: Replacement of Phe3 in the endogenous δ‐opioid selective peptide deltorphin I with four optically pure stereoisomers of the topographically constrained, highly hydrophobic novel amino acid β‐isopropylphenylalanine (β‐iPrPhe) produced four pharmacologically different deltorphin I peptidomimetics. Radiolabeled ligand‐binding assays and in vitro biological evaluation indicate that the stereoconfiguration of the iPrPhe residue plays a crucial role in determining the binding affinity, bioactivity and selectivity of β‐iPrPhe3]deltorphin I analogs: a (2S,3R) configuration of the iPrPhe3 residue in β‐iPrPhe3]deltorphin I provided the most desirable biological properties with binding affinity (IC50 = 2 n m ), bioassay potency (IC50 = 1.23 n m in MVD assay) and exceptional selectivity for the δ‐opioid receptor over the µ‐opioid receptor (30 000). Further conformational studies based on two‐dimensional NMR and computer‐assisted molecular modeling suggested a model for the possible bioactive conformation in which the Tyr1 and (2S,3R)‐β‐iPrPhe3 residues adopt trans side‐chain conformations, and the linear peptide backbone favors a distorted β‐turn conformation. |
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Keywords: | bioactive conformation β ‐isopropylphenylalanine deltorphin NMR opioid peptides |
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