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

• Published in: Chemistry : 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
• Language: English
• Published: Germany Blackwell Publishing Ltd 04.10.2016; Wiley Subscription Services, Inc
• Subjects: Affinity; Binding; bioorganometallic chemistry; Chemistry; Conjugates; In vitro testing; metal-peptide conjugates; Metalorganic compounds; Narcotics; opioid receptors; Peptides; Receptors; structural biology; opioid receptors; peptides; bioorganometallic chemistry; structural biology; metal-peptide conjugates
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201602432

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).