Identification of a μ-δ opioid receptor heteromer-biased agonist with antinociceptive activity

G protein-coupled receptors play a pivotal role in many physiological signaling pathways. Mounting evidence suggests that G protein-coupled receptors, including opioid receptors, form dimers, and dimerization is necessary for receptor maturation, signaling, and trafficking. However, the physiological role of dimerization in vivo has not been well-explored because of the lack of tools to study these dimers in endogenous systems. To address this problem, we previously generated antibodies to mu-delta opioid receptor (mu OR-delta OR) dimers and used them to study the pharmacology and signaling by this heteromer. We also showed that the heteromer exhibits restricted distribution in the brain and that its abundance is increased in response to chronic morphine administration. Thus, the mu OR-delta OR heteromer represents a potentially unique target for the development of therapeutics to treat pain. Here, we report the identification of compounds targeting mu OR-delta OR heteromers through high-throughput screening of a small-molecule library. These compounds exhibit activity in mu OR-delta OR cells but not mu OR or delta OR cells alone. Among them, CYM51010 was found to be a mu OR-delta OR-biased ligand, because its activity is blocked by the mu OR-delta OR heteromer antibody. Notably, systemic administration of CYM51010 induced antinociceptive activity similar to morphine, and chronic administration of CYM51010 resulted in lesser antinociceptive tolerance compared with morphine. Taken together, these results suggest that CYM51010, a mu OR-delta OR-biased ligand, could serve as a scaffold for the development of a unique type (heteromer-biased) of drug that is more potent and without the severe side effects associated with conventional clinical opioids.