Application of the message-address concept to the docking of naltrexone and selective naltrexone-derived opioid antagonists into opioid receptor models

Thomas G. Metzger, M. Germana Paterlini, Philip S. Portoghese, David M. Ferguson

Research output: Contribution to journalArticlepeer-review

83 Scopus citations

Abstract

A binding site model for the opioid family of G-protein coupled receptors (GPCRs) is proposed based on the message-address concept of ligand recognition. Using ligand docking studies of the universal opioid antagonist, naltrexone, the structural basis for 'message' recognition is explored across all three receptor types, μ, δ, and κ. The binding mode proposed and basis for selectivity are also rationalized using the naltrexone-derived ligands, naltrindole (NTI) and norbinaltorphimine (nor BNI). These ligands are docked to the receptor according to the common naltrexone core or message. The resulting orientation places key 'address' elements in close proximity to amino acid residues critical to selectivity among receptor types. Selectivity is explained by sequence differences in the μ, δ, and κ receptors at these recognition points. Support for the model is derived from site directed mutagenesis studies and ligand binding data for the opioid receptors and other related GPCRs.

Original languageEnglish (US)
Pages (from-to)1287-1294
Number of pages8
JournalNeurochemical Research
Volume21
Issue number11
DOIs
StatePublished - Nov 1996

Keywords

  • Opioid receptor
  • ligand docking
  • naltrexone

Fingerprint

Dive into the research topics of 'Application of the message-address concept to the docking of naltrexone and selective naltrexone-derived opioid antagonists into opioid receptor models'. Together they form a unique fingerprint.

Cite this