Journal
AAPS JOURNAL
Volume 8, Issue 1, Pages E153-E159Publisher
SPRINGER
DOI: 10.1208/aapsj080118
Keywords
G-protein-coupled receptors; dimerization; allosteric interaction; high-throughput screening (HTS); secreted alkaline phosphatase (SEAP)
Categories
Funding
- NIDA NIH HHS [DA08863, DA19521] Funding Source: Medline
- NATIONAL INSTITUTE ON DRUG ABUSE [R56DA008863, K05DA019521, R01DA008863] Funding Source: NIH RePORTER
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G-protein-coupled receptors are a major target for the development of new marketable drugs. A growing number of studies have shown that these receptors could bind to their ligands, signal, and be internalized as dimers. Most of the evidence comes from in vitro studies, but recent studies using animal models support an important role for dimerization in vivo and in human pathologies. It is therefore becoming highly relevant to include dimerization in screening campaigns: the increased complexity reached by the ability to target 2 receptors should lead to the identification of more specific hits that could be developed into drugs with fewer side effects. In this review, we have summarized results from a series of studies characterizing the properties of G-protein-coupled receptor dimers using both in vitro and in vivo systems. Since opioid receptors exist as dimers and heterodimerization modulates their pharmacology, we have used them as a model system to develop strategies for the identification of compounds that will specifically bind and activate opioid receptor heterodimers: such compounds could represent the next generation of pain relievers with decreased side effects, including reduced drug abuse liability.
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