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

Ivone Gomes, Wakako Fujita, Achla Gupta, Adrian S. Saldanha, Ana Negri, Christine E. Pinello, Edward Roberts, Marta Filizola, Peter Hodder, Lakshmi A. Devi

Research output: Contribution to journalArticlepeer-review

109 Scopus citations


G protein-coupled receptors play a pivotal role inmany physiological signaling pathways. Mounting evidence suggests that G proteincoupled 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 μ-δ opioid receptor (μOR-δOR) 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 μOR-δOR heteromer represents a potentially unique target for the development of therapeutics to treat pain. Here, we report the identification of compounds targeting μOR-δOR heteromers through high-throughput screening of a small-molecule library. These compounds exhibit activity in μOR-δOR cells but not μOR or dOR cells alone. Among them, CYM51010 was found to be a μOR-δOR-biased ligand, because its activity is blocked by the μOR-δOR heteromer antibody. Notably, systemic administration of CYM51010 induced antinociceptive activity similar to morphine, and chronic administration of CYM51010 resulted in lesser antinociceptive tolerance comparedwithmorphine. Taken together, these results suggest that CYM51010, a μOR-δOR-biased ligand, could serve as a scaffold for the development of a unique type (heteromer-biased) of drug that ismore potent and without the severe side effects associated with conventional clinical opioids.

Original languageEnglish
Pages (from-to)12072-12077
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number29
StatePublished - 16 Jul 2013


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