RT Journal Article SR Electronic T1 The third extracellular loop of the human delta-opioid receptor determines the selectivity of delta-opioid agonists. JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1619 OP 1624 VO 50 IS 6 A1 E V Varga A1 X Li A1 D Stropova A1 T Zalewska A1 R S Landsman A1 R J Knapp A1 E Malatynska A1 K Kawai A1 A Mizusura A1 H Nagase A1 S N Calderon A1 K Rice A1 V J Hruby A1 W R Roeske A1 H I Yamamura YR 1996 UL http://molpharm.aspetjournals.org/content/50/6/1619.abstract AB In the present study, we replaced the third extracellular loop of the human delta-opioid receptor with that of the human mu-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 delta-selective peptide agonists cyclo[D-Pen2,4'Cl-Phe4,D-Pen5]enkephalin and deltorphin II and the delta-selective nonpeptide agonists SNC 121 and (-)TAN 67. The affinities of the mu-selective peptide agonist [D-Ala2-MePhe4-Gly-ol5]enkephalin and the mu-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.