In vivo and in vitro evaluation of novel μ-opioid receptor agonist compounds

Eur J Pharmacol. 2015 Nov 15:767:193-200. doi: 10.1016/j.ejphar.2015.10.025. Epub 2015 Oct 20.


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.

Keywords: Cross-tolerance; DAMGO (PubChem CID:5462471); High-throughput screening; Morphine (PubChem CID:5464110); NPD26 (PubChem CID:3129829); NPD3000 (PubChem CID:1788462); NPD48 (PubChem CID:3132838); NPD660, GUM1 (PubChem CID:3884637); NPD711 (PubChem CID:11870750); NPD85 (PubChem CID:78246253); Opioid receptor; Opioid rotation; Receptor-Gα fusion protein; TRV130 (PubChem CID:66553195); Transgenic silkworm.

MeSH terms

  • 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


  • Analgesics, Opioid
  • Benzylamines
  • Biological Products
  • GUM1 compound
  • OPRM1 protein, human
  • Pyrans
  • Receptors, Opioid, mu
  • Sulfur Radioisotopes
  • Guanosine 5'-O-(3-Thiotriphosphate)