BW373U86, a non-peptide δ opioid agonist with novel receptor-protein-mediated actions

Abstract

BW373U86 (BW373) is a potent and highly selective non-peptide agonist for δ opioid receptors. In order to determine its ability to activate G-protein-linked second messenger systems, the effects of BW373 on inhibition of adenylyl cyclase (AC) and stimulation of low K m GTPase activity were examined. In rat striatal membranes, BW373 inhibited basal AC in a GTP-dependent, δ-selective manner, with maximal inhibition similar to the δ agonist DSLET. However, BW373 was 75 times more potent than DSLET. In NG108-15 membranes, BW373 inhibited AC with a 5-fold lower IC 50 value than DSLET, and stimulated low K m GTPase with equal potency to DSLET. Although DSLET and BW373 were also equipotent in displacing [ 3H]diprenorphine binding to NG108-15 cell membranes in the absence of sodium and guanine nucleotides, BW373 was unique in displaying no change in binding affinity in the presence of sodium and guanine nucleotides. These results show how lack of guanine nucleotide regulation of the binding of a full agonist to a G-protein-coupled receptor affects agonist potency.