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.
Chemistry
; 22(41): 14605-10, 2016 Oct 04.
Article
em En
| MEDLINE
| ID: mdl-27553294
ABSTRACT
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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Rênio
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Receptores Opioides mu
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Peptídeos Opioides
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Complexos de Coordenação
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Analgésicos Opioides
Limite:
Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article