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 (D24M) producing the highest MDOR potency/affinity (<1 nM) and selectivity
(≥89-fold). We further evaluated D24M in mice
and observed that D24M 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 D24M sharply reduced withdrawal behavior
in models of acute and chronic morphine dependence. These findings
suggest that D24M is a first-in-class high-potency MDOR-selective
antagonist both in vitro and in vivo.