Structure-activity relationships and discovery of a G protein biased μ opioid receptor ligand, [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro-[4.5]decan-9-yl]ethyl})amine (TRV130), for the treatment of acute severe pain
| Autor: | Yuan Catherine C K, Philip Pitis, Michael Koblish, Xiao-Tao Chen, Dimitar Gotchev, Guodong Liu, Dennis Yamashita, Scott M. DeWire, Aimee L. Crombie, David H. Rominger, Conrad L. Cowan, Jonathan D. Violin |
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| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_specialty
G protein medicine.drug_class Analgesic Oliceridine Receptors Opioid mu Thiophenes Pharmacology Severity of Illness Index chemistry.chemical_compound Mice Structure-Activity Relationship Therapeutic index Opioid receptor GTP-Binding Proteins Internal medicine Drug Discovery medicine Animals Humans Spiro Compounds Receptor G protein-coupled receptor Analgesics Molecular Structure Chemistry Acute Pain Rats Disease Models Animal Endocrinology HEK293 Cells Opioid Models Chemical Molecular Medicine medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 56(20) |
| ISSN: | 1520-4804 |
| Popis: | The concept of "ligand bias" at G protein coupled receptors has been introduced to describe ligands which preferentially stimulate one intracellular signaling pathway over another. There is growing interest in developing biased G protein coupled receptor ligands to yield safer, better tolerated, and more efficacious drugs. The classical μ opioid morphine elicited increased efficacy and duration of analgesic response with reduced side effects in β-arrestin-2 knockout mice compared to wild-type mice, suggesting that G protein biased μ opioid receptor agonists would be more efficacious with reduced adverse events. Here we describe our efforts to identify a potent, selective, and G protein biased μ opioid receptor agonist, TRV130 ((R)-30). This novel molecule demonstrated an improved therapeutic index (analgesia vs adverse effects) in rodent models and characteristics appropriate for clinical development. It is currently being evaluated in human clinical trials for the treatment of acute severe pain. |
| Databáze: | OpenAIRE |
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