Synthesis and Evaluation of a Novel Bivalent Selective Antagonist for the Mu-Delta Opioid Receptor Heterodimer that Reduces Morphine Withdrawal in Mice

A major limitation in the study of the mu-delta opioid receptor heterodimer (MDOR) is that few selective pharmacological tools exist and no heteromer-selective antagonists. We thus designed a series of variable-length (15–41 atoms) bivalent linked peptides with selective but moderate/low-affinity pharmacophores for the mu and delta opioid receptors. We observed a U-shaped MDOR potency/affinity profile in vitro, with the 24-atom spacer length (<b>D24M</b>) producing the highest MDOR potency/affinity (<1 nM) and selectivity (≥89-fold). We further evaluated <b>D24M</b> in mice and observed that <b>D24M</b> dose-dependently antagonized tail flick antinociception produced by the MDOR agonists CYM51010 and Deltorphin-II, without antagonizing the monomer agonists DAMGO and DSLET. We also observed that <b>D24M</b> sharply reduced withdrawal behavior in models of acute and chronic morphine dependence. These findings suggest that <b>D24M</b> is a first-in-class high-potency MDOR-selective antagonist both in vitro and in vivo