RRC ID 36274
著者 Nikaido Y, Kurosawa A, Saikawa H, Kuroiwa S, Suzuki C, Kuwabara N, Hoshino H, Obata H, Saito S, Saito T, Osada H, Kobayashi I, Sezutsu H, Takeda S.
タイトル In vivo and in vitro evaluation of novel μ-opioid receptor agonist compounds.
ジャーナル Eur J Pharmacol
Abstract Opioids are the most effective and widely used drugs for pain treatment. Morphine is an archetypal opioid and is an opioid receptor agonist. Unfortunately, the clinical usefulness of morphine is limited by adverse effects such as analgesic tolerance and addiction. Therefore, it is important to study the development of novel opioid agonists as part of pain control. The analgesic effects of opioids are mediated by three opioid receptors, namely opioid μ-, δ-, and κ-receptors. They belong to the G protein-coupled receptor superfamily and are coupled to Gi proteins. In the present study, we developed a ligand screening system to identify novel opioid μ-receptor agonists that measures [(35)S]GTPγS binding to cell membrane fractions prepared from the fat body of transgenic silkworms expressing μ-receptor-Gi1α fusion protein. We screened the RIKEN Natural Products Depository (NPDepo) chemical library, which contains 5848 compounds, and analogs of hit compounds. We successfully identified a novel, structurally unique compound, that we named GUM1, with agonist activity for the opioid μ-receptor (EC50 of 1.2 µM). The Plantar Test (Hargreaves' Method) demonstrated that subcutaneous injection of 3mg/kg of GUM1 into wild-type rats significantly extended latency time. This extension was also observed in a rat model of morphine tolerance and was inhibited by pre-treatment of naloxone. The unique molecular skeleton of GUM1 makes it an attractive molecule for further ligand-opioid receptor binding studies.
巻・号 767
ページ 193-200
公開日 2015-11-15
DOI 10.1016/j.ejphar.2015.10.025
PII S0014-2999(15)30306-X
PMID 26476280
MeSH Analgesics, Opioid / agonists Analgesics, Opioid / pharmacology Animals Animals, Genetically Modified Benzylamines / agonists* Benzylamines / pharmacology* Biological Products / pharmacology* Bombyx Drug Tolerance Guanosine 5'-O-(3-Thiotriphosphate) / metabolism Humans Male Pain Measurement / drug effects Pyrans / agonists* Pyrans / pharmacology* Radioligand Assay Rats Receptors, Opioid, mu / agonists* Receptors, Opioid, mu / genetics Sulfur Radioisotopes / metabolism
IF 3.263
引用数 6
WOS 分野 PHARMACOLOGY & PHARMACY
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