It could be an important step forward in the improvement of pain therapy: Thanks to newly developed molecular probes, the behavior of individual opioid receptors can now be studied in detail.
Strong painkillers are very important in the management of patients with cancer and heart attack or requiring surgery. They extert their effect by binding to so-called opioid receptors in the body.
These painkillers have excellent efficacy, but also severe side effects. On the one hand, there is the danger of dependency, on the other hand, patients may become tolerant – i.e. the effectiveness of the drugs decreases with repeated use. This means that the dose must be increased over time to achieve the same effect.
Basic research on opioid receptors
Painkillers with less drastic undesirable effects and equally good efficacy would therefore be highly desirable. Michael Decker, Professor of Pharmaceutical and Medicinal Chemistry at Julius-Maximilians-Universität (JMU) Würzburg, in Bavaria, Germany, is pursuing research in this field. Among other things, his team wants to expand the basic knowledge about opioid receptors.
Decker now presents new findings in this field in the journal "Angewandte Chemie" together with Sébastien Granier from the Institut de Génomique Fonctionelle in Montpellier, Peter Gmeiner from the University of Erlangen-Nuremberg, and as main collaborator Professor Davide Calebiro from the University of Birmingham, UK. The JMU PhD students Christian Gentzsch, Kerstin Seier, and Antonios Drakopoulos were also involved in the work.
The receptors form short-lived pairs
The team dealt with a question that has been highly debated in the field so far. "It is still unclear whether the analgesic effect of opioids is mediated by individual receptors or whether it is necessary for the receptors to aggregate into pairs or larger molecular complexes," said Decker. Evidence has already been found for all these possibilities.
"Our results help reconciling some of the previously contradictory observations," says Davide Calebiro, who until recently was a researcher at JMU. "We found that most opioid receptors exist as individual entities in the cell membrane. However, a small proportion forms pairs of two. Although the lifespan of these pairs is short, they might contribute to the function of this important family of receptors."
Journal classifies work as "Highly Important“
This finding might be very important: "There is evidence that the receptor pairs have different pharmacological effects than individual receptors," said Decker. Therefore, it might be possible to develop new painkillers with a more favourable effect profile on the basis of this knowledge.
Due to the importance of these new findings, "Angewandte Chemie" has classified the publication of the JMU researchers as "highly important". It is freely available on the Web. In addition, the work was selected for one of the journal covers.
Highly selective ligands developed
The research team came to its conclusion because it had previously developed highly selective fluorescent ligands for a subtype of the receptors, the so-called mu opioid receptor (MOR). This is the most important of the three receptor subtypes and is responsible for the desired pain-relieving but also for the addictive effect. The new ligands can be used as molecular probes to label the receptor highly specifically and to observe its behaviour in living cells using single-molecule fluorescence microscopy.
The researchers are now working on the production of fluorescent ligands for the other two receptor subtypes (delta and kappa; DOR and KOR) in order to analyse their behaviour in the cell membrane as well. This has already been achieved with KOR (A. Drakopoulos et al., Journal of Medicinal Chemistry 2020, in print).
This work was financially supported by the Elite Network of Bavaria within the framework of the International PhD Program "Receptor Dynamics". Other sponsors were the Wellcome Trust, the German Research Foundation (DFG) and the National Institutes of Health (USA).
Prof. Dr. Michael Decker, Institute for Pharmacy and Food Chemistry, University of Würzburg, T +49 931 31-89676, email@example.com
Prof. Davide Calebiro, Institute of Metabolism and Systems Research, University of Birmingham, T +44 121 414 3928, firstname.lastname@example.org
Selective and Wash-Resistant Fluorescent Dihydrocodeinone Derivatives Allow Single-Molecule Imaging of mu-Opioid Receptor Dimerisation, Applied Chemistry, DOI 10.1002/ange.201912683, and Applied Chemistry International Edition, February 26, 2020, DOI 10.1002/anie.201912683
https://onlinelibrary.wiley.com/doi/full/10.1002/anie.201912683 Open Access publication in "Angewandte Chemie"
https://onlinelibrary.wiley.com/doi/full/10.1002/anie.202002281 Link to the cover of the magazine
https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b02011 Publication in the Journal of Medicinal Chemistry, 11 March 2020
Robert Emmerich | Julius-Maximilians-Universität Würzburg
Cellular protein shredders for the fight against cancer
25.03.2020 | Rheinische Friedrich-Wilhelms-Universität Bonn
Teamwork in a cell
25.03.2020 | Max Delbrück Center for Molecular Medicine in the Helmholtz Association
Researchers at the University of Zurich show that different stem cell populations are innervated in distinct ways. Innervation may therefore be crucial for proper tissue regeneration. They also demonstrate that cancer stem cells likewise establish contacts with nerves. Targeting tumour innervation could thus lead to new cancer therapies.
Stem cells can generate a variety of specific tissues and are increasingly used for clinical applications such as the replacement of bone or cartilage....
An international research team led by Kiel University develops an extremely porous material made of "white graphene" for new laser light applications
With a porosity of 99.99 %, it consists practically only of air, making it one of the lightest materials in the world: Aerobornitride is the name of the...
Researchers at Graz University of Technology have developed a framework by which wireless devices with different radio technologies will be able to communicate directly with each other.
Whether networked vehicles that warn of traffic jams in real time, household appliances that can be operated remotely, "wearables" that monitor physical...
Terahertz waves are becoming ever more important in science and technology. They enable us to unravel the properties of future materials, test the quality of...
An international team of researchers from Switzerland, Germany, the USA and Great Britain has uncovered an anomalous metallic behavior in an otherwise insulating ceramic material. The team used ultrashort light pulses with a wide range of colors to watch what happens when the insulating quasi two-dimensional material La2CuO4 (LCO) becomes a three-dimensional metal through laser irradiation. Surprisingly, the researchers found that specific vibrations of the crystal lattice are involved in this metallization process. A careful computational investigation revealed that the same vibrations that show up in this ultrafast movie can destabilize the insulating behavior all by themselves.
The condensed-matter physics world was shaken up when high-temperature superconductivity was reported in a copper oxide material in 1986 by Alex Müller and...
23.03.2020 | Event News
03.03.2020 | Event News
02.03.2020 | Event News
25.03.2020 | Earth Sciences
25.03.2020 | Power and Electrical Engineering
25.03.2020 | Life Sciences