A Blocking Group Scan Using a Spherical Organometallic Complex Identifies an Unprecedented Binding Mode with Potent Activity In Vitro and In Vivo for the Opioid Peptide Dermorphin

Herein, the selective enforcement of one particular receptor‐ligand interaction between specific domains of the μ‐selective opioid peptide dermorphin and the μ opioid receptor is presented. For this, a blocking group scan is described which exploits the steric demand of a bis(quinolinylmethyl)amine...

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Published inChemistry : a European journal Vol. 22; no. 41; pp. 14605 - 14610
Main Authors Strack, Martin, Bedini, Andrea, Yip, King T., Lombardi, Sara, Siegmund, Daniel, Stoll, Raphael, Spampinato, Santi M., Metzler-Nolte, Nils
Format Journal Article
LanguageEnglish
Published Germany Blackwell Publishing Ltd 04.10.2016
Wiley Subscription Services, Inc
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Summary:Herein, the selective enforcement of one particular receptor‐ligand interaction between specific domains of the μ‐selective opioid peptide dermorphin and the μ opioid receptor is presented. For this, a blocking group scan is described which exploits the steric demand of a bis(quinolinylmethyl)amine rhenium(I) tricarbonyl complex conjugated to a number of different, strategically chosen positions of dermorphin. The prepared peptide conjugates lead to the discovery of two different binding modes: An expected N‐terminal binding mode corresponds to the established view of opioid peptide binding, whereas an unexpected C‐terminal binding mode is newly discovered. Surprisingly, both binding modes provide high affinity and agonistic activity at the μ opioid receptor in vitro. Furthermore, the unprecedented C‐terminal binding mode shows potent dose‐dependent antinociception in vivo. Finally, in silico docking studies support receptor activation by both dermorphin binding modes and suggest a biological relevance for dermorphin itself. Relevant ligand‐protein interactions are similar for both binding modes, which is in line with previous protein mutation studies. Decoration of the opioid peptide dermorphin with a spherical organometallic complex at strategically chosen positions resulted in the discovery of a new, unexpected C‐terminal binding mode with exceptionally high affinity to the μ opioid receptor and potent agonistic activity up to the in vivo level (see figure).
Bibliography:istex:3613383D743F52702DC00C1EE56CCED16EC3BFE6
ark:/67375/WNG-B4D3HM6V-P
Fonds der Chemischen Industrie
ArticleID:CHEM201602432
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201602432