The third extracellular loop of the human δ-opioid receptor determines the selectivity of δ-opioid agonists

Eva V. Varga, Xiaoping Li, Dagmar Stropova, Teresa Zalewska, Robert S. Landsman, Richard J. Knapp, Ewa Malatynska, Kohji Kawai, Akira Mizusura, Hiroshi Nagase, Silvia N. Calderon, Kenner Rice, Victor J. Hruby, William R. Roeske, Henry I. Yamamura

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

In the present study, we replaced the third extracellular loop of the human δ-opioid receptor with that of the human μ-opioid receptor. A modified polymerase chain reaction overlap extension method was used to achieve the exact splicing in the chimera to show the importance of the extracellular loop in ligand binding without interference from transmembrane substitutions. The replacement of the third extracellular loop did not alter the affinity of [3H]diprenorphine but caused a dramatic decrease in the affinity of both the δ-selective peptide agonists cyclo[D-Pen2,4'Cl- Phe4,D-Pen5]enkephalin and deltorphin II and the δ-selective nonpeptide agonists SNC 121 and (-)TAN 67. The affinities of the μ-selective peptide agonist [D-Ala2-MePhe4-Gly-ol5]enkephalin and the μ-preferring nonpeptide agonist morphine were not affected. Site-directed mutagenesis studies show that the mechanism of ligand recognition might be different for each structural class of opioid ligands.

Original languageEnglish (US)
Pages (from-to)1619-1624
Number of pages6
JournalMolecular pharmacology
Volume50
Issue number6
StatePublished - Dec 1 1996

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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