Differential signaling properties at the kappa opioid receptor of 12-epi-salvinorin A and its analogues
| Autor: | John M. Streicher, William A. Carlezon, Bruce M. Cohen, Lee-Yuan Liu-Chen, Laura M. Bohn, Justin S. Potuzak, Chad E. Groer, Cécile Béguin, Wei Xu |
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| Rok vydání: | 2011 |
| Předmět: |
Agonist
medicine.drug_class Clinical Biochemistry Molecular Conformation Pharmaceutical Science Pharmacology Biochemistry κ-opioid receptor Partial agonist Article Diterpenes Clerodane chemistry.chemical_compound Structure-Activity Relationship Cell Line Tumor Drug Discovery medicine Humans Receptor Molecular Biology Dose-Response Relationship Drug Salvinorin Receptors Opioid kappa Organic Chemistry Ligand (biochemistry) Salvinorin A chemistry Opioid Molecular Medicine medicine.drug Signal Transduction |
| Zdroj: | Bioorganicmedicinal chemistry letters. 22(2) |
| ISSN: | 1464-3405 |
| Popis: | The kappa opioid receptor (KOPR) has been identified as a potential drug target to prevent or alter the course of mood, anxiety and addictive disorders or reduce response to stress. In a search for highly potent and selective KOPR partial agonists as pharmacological tools, we have modified 12-epi-salvinorin A, a compound which we have previously observed to be a KOPR partial agonist. Five analogues of 12-epi-salvinorin A were synthesized and their effects on G protein activation as well as β-arrestin2 recruitment were evaluated. Only 12-epi-salvinorin A (1) partially activated signaling through G proteins, yet acted as a full agonist in the β-arrestin 2 DiscoveRx assay. Other salvinorin analogues tested in these functional assays were full agonists in both assays of KOPR activation. By comparison, the non-selective opioid ligand nalbuphine, known to be a partial agonist for G-protein activation, was also a partial agonist for the β-arrestin mediated signaling pathway activated through KOPR. |
| Databáze: | OpenAIRE |
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