Opioid Research Group
The major research direction of the ‘Opioid Research Group’ is dedicated to the development of innovative ligands targeting opioid receptors (mu, kappa and delta), as effective and safer therapeutics for human diseases where the opioid system plays a key role. Our work covers areas of basic and applied research in medicinal chemistry and pharmacology of the opioid system. The group has a constant focus on the discovery of new opioid analgesics acting at mu and kappa opioid receptors, as alternatives to currently used drugs for an efficient and improved pain management. The research program is also addressing the identification and characterization of active opioid ligands at the in vitro and in vivo levels as potential drugs for the treatment of gastrointestinal disorders (IBD and OBD), cancer and neurological conditions (epilepsy). Additionally, the group is developing selective opioid ligands as research tools for understanding the basic biology of opioid receptor signaling in vitro and in vivo.
Central aims of our projects include modulation of the ligand/opioid receptor system in specific pathological conditions, structure-functional-activity relationships, understanding the mechanism of opioid actions and the linkage between therapeutic effects (i.e. analgesia, anti-inflammatory, anti-tumor, anti-epileptic/anti-seizure), side effects and molecular mode of action. The specific research goals include drug design and synthesis, pharmacological testing and SAR of ligands with distinct properties (agonism, antagonism, partial agonism, biased agonism, and ligands acting at multiple opioid/non-opioid receptors) or selective site of action (central, peripheral).
Our drug development strategies addresses structurally-diverse compounds (natural, naturally-derived and synthetic compounds; small molecules and peptides) including screening for binding and signaling profiles at opioid receptors together with mechanistic studies. More than 1,000 compounds have been synthesized and biologically characterized according to protocols established in our laboratories. The applied screening platforms include state-of-the-art biochemical and cell-based assays, and pharmacological and disease animal models are used to establish the in vivo therapeutic efficacy and profiling for side effects. Multidisciplinary and synergistic approaches are merged through national and international collaborations, where advanced methodologies are applied in the specific research program.
The Opioid Research Group is member of CMBI (https://www.uibk.ac.at/cmbi/)
NEWS & PRESS
2024
Mariana Spetea is member of the Sientific committee of the “4th Molecules Medicinal Chemistry Symposium - Harnessing the Power of New Drug Modalities (MMCS2024)” to be held in Barcelona, Spain from 24 to 26 of April 2024 https://sciforum.net/event/MMCS2024
2022
Mariana Spetea is member of the Conference committee of the “3rd Molecules Medicinal Chemistry Symposium - Shaping Medicinal Chemistry for the New Decade (MMCS2022)” to be held in Rome, Italy, from 27 to 29 July 2022 (https://mmcs2022.sciforum.net)
2021
Mariana Spetea was appointed as Associated Editor of Frontiers in Drug Discovery (Section, Neurological Drugs) (https://www.frontiersin.org/)
December 2021
Über 70 herausragende Forscher*innen
(https://www.uibk.ac.at/newsroom/ueber-70-herausragende-forscher-innen.html.de)
2021
Mariana Spetea contributes with two chapters to the book “The kappa opioid receptor” edited by Lee-Yuan Liu-Chen and Saadet Inan.
September 2019
Mariana Spetea and Helmut Schmidhammer are Guest Editors of a Special Issue of Molecules: Opioids and their receptors: Present and emerging concepts in opioid drug discovery
(https://www.mdpi.com/journal/molecules/special_issues/Opioid_Drug)
September 2019
Maria Dumitrascuta wins the Oral Presentation Prize at the Joint Meetings of the Austrian Neuroscience Association (ANA) and the Austrian Pharmacological Society (APHAR) 2019, in Innsbruck
(https://www.uibk.ac.at/newsroom/neuroscience-meeting-in-innsbruck.html.de)
July 2018
New ways to turnoff side effects
(https://www.uibk.ac.at/newsroom/neue-wege-zur-ausschaltung-von-nebenwirkungen-.html.de)
January 2017
Pain is a disease state in its own right
(https://www.diepresse.com/5153742/bdquoschmerz-ist-eine-eigene-krankheitldquo)
April 2016
The key to a better pain therapy
(https://issuu.com/zielgruppenverlag.at/docs/innovation_1604)
RECENT PUBLICATIONS
Muratspahic E., White A.M., Ciotu C.I., Hochrainer N., Tomasevic N., Koehbach J., Lewis R.J., Spetea M., Fischer M.J.M., Craik D.J., Gruber C.W. Development of a selective peptide κ‑opioid receptor antagonist by late-stage functionalization with cysteine staples. J. Med. Chem. (2023) https://doi.org/10.1021/acs.jmedchem.3c00426
Schmidhammer H., Al-Khrasani M., Fürst S., Spetea M. Peripheralization strategies applied to morphinans and implications for improved treatment of pain. Molecules 28:4761 (2023). https://doi.org/10.3390/molecules28124761
Dumitrascuta M., Martin C., Ballet S., Spetea M. Bifunctional peptidomimetic G protein-biased mu-opioid receptor agonist and neuropeptide FF receptor antagonist KGFF09 shows efficacy in visceral pain without rewarding effects after subcutaneous administration in mice. Molecules 27:8785 (2022). https://doi.org/10.3390/molecules27248785
Kaufmann J., Blum N.K., Nagel F., Schuler A., Drube J., Degenhart C., Engel J., Eickhoff J.E., Dasgupta P., Fritzwanker S., Guastadisegni M., Schulte C., Miess-Tanneberg E., Maric H.M., Spetea M., Kliewer A., Baumann M., Klebl B., Reinscheid R.K., Hoffmann C., Schulz S. A bead-based GPCR phosphorylation immunoassay for high-throughput ligand profiling and GRK inhibitor screening. Commun. Biol. 5:1206 (2022). doi: 10.1101/2022.07.25.501346
Puls K., Olivé-Marti A.L., Pach S., Pinter B., Erli F., Wolber G., Spetea M. In vitro, in vivo and in silico characterization of a novel kappa-opioid receptor antagonist. Pharmaceuticals (Basal) 15:680 (2022). doi: 10.3390/ph15060680
Puls K., Schmidhammer H., Wolber G., Spetea M. Mechanistic characterization of the pharmacological profile of HS-731, a peripherally acting opioid analgesic at the µ-, δ-, κ-opioid and nociceptin receptors. Molecules 27:919 (2022). doi: 10.3390/molecules27030919
Paul A.K., Smith C.M., Rahmatullah M., Nissapatorn V., Wilairatana P., Spetea M., Gueven N., Dietis N. Opioid analgesia and opioid-induced adverse effects: A review. Pharmaceuticals (Basal) 14:1091 (2021). doi: 10.3390/ph14111091
Spetea M., Schmidhammer H. Recent chemical and pharmacological developments on 14-oxygenated-N-methylmorphinan-6-ones. Molecules 26:5677 (2021). doi: 10.3390/molecules26185677
Fritzwanker S., Moulédous L., Mollereau C., Froment C., Burlet-Schiltz O., Effah F., Bailey A., Spetea M., Reinscheid R.K., Schulz S., Kliewer A. HA-MOP knockin mice express the canonical µ-opioid receptor but lack detectable splice variants. Commun. Biol. 4:1070 (2021). doi: 10.1038/s42003-021-02580-6
Dumitrascuta M., Bermudez M., Trovato O., De Neve J., Ballet S., Wolber G., Spetea M. Antinociceptive efficacy of the µ-opioid/nociceptin peptide-based hybrid KGNOP1 in inflammatory pain without rewarding effects in mice: an experimental assessment and molecular docking. Molecules 26:3267 (2021). doi: 10.3390/molecules26113267
Cahill C., Tejeda H.A., Spetea M., Chen C., Liu-Chen L.Y. Fundamentals of the dynorphins/kappa opioid receptor system: From distribution to signaling and function. Handb. Exp. Pharmacol. 271:3-21 (2021) doi: 10.1007/164_2021_433
Spetea M., Schmidhammer H. Kappa opioid receptor ligands and pharmacology: diphenethylamines, a class of structurally distinct, selective kappa opioid ligands. Handb. Exp. Pharmacol. 271:163-195 (2021) doi: 10.1007/164_2020_431
Schmidhammer H., Erli F., Guerrieri E., Spetea M. Development of diphenethylamines as selective kappa opioid receptor ligands and their pharmacological activities. Molecules 25:5092 (2020). doi: 10.3390/molecules25215092
Gonzalez S., Dumitrascuta M., Eiselt E., Louis S., Kunze L., Blasiol A., Vivancos M., Previti S., Dewolf E., Martin C., Tourwé D., Cavelier F., Gendron L., Sarret P., Spetea M., Ballet S. Optimized opioid-neurotensin multitarget peptides: from design to structure-activity relationship studies. J. Med. Chem. 63:12929-12941 (2020). doi: 10.1021/acs.jmedchem.0c01376
Kaserer T., Steinacher T., Kainhofer R., Erli F., Sturm S., Waltenberger B., Schuster D., Spetea M. Identification and characterization of plant-derived alkaloids, corydine and corydaline, as novel mu opioid receptor agonists. Sci. Rep. 10:13804 (2020). doi: 10.1038/s41598-020-70493-1
Dumitrascuta M., Bermudez M., Ben Haddou T., Guerrieri E., Schläfer L., Ritsch A., Hosztafi S., Lantero A., Kreutz C., Massotte D., Schmidhammer H., Wolber G., Spetea M. N-Phenethyl substitution in 14-methoxy-N-methylmorphinan-6-ones turns selective µ opioid receptor ligands into dual µ/δ opioid receptor agonists. Sci. Rep. 10:5653 (2020). doi: 10.1038/s41598-020-62530-w
Spetea M., Rief B. S., Ben Haddou T., Fink M., Kristeva E., Mittendorfer H., Haas S., Hummer N., Follia V., Guerrieri E., Asim M. F., Sturm S., Schmidhammer H. Synthesis, biological and structural explorations of new zwitterionic derivatives of 14-O-methyloxymorphone, as potent mu/delta opioid agonists and peripherally selective antinociceptives. J. Med. Chem. 62:641-653 (2019). doi: 10.1021/acs.jmedchem.8b01327
Martin C., Dumitrascuta M., Mannes M., Lantero A., Bucher D., Walker K., Van Wanseele Y., Oyen E., Hernot S., Van Eeckhaut A., Madder A.,* Hoogenboom R., Spetea M., Ballet S. Biodegradable amphipathic peptide hydrogels as extended-release system for opioid peptides. J. Med. Chem. 61:9784 -9789 (2018). doi: 10.1021/acs.jmedchem.8b01282.
Lattanzi R., Rief S., Schmidhammer H., Negri L., Spetea M. In vitro and in vivo pharmacological activities of 14-O-phenylpropyloxymorphone, a potent mixed mu/delta/kappa-opioid receptor agonist with reduced constipation in mice. Front. Pharmacol. 9:1002 (2018). doi: 10.3389/fphar.2018.01002
Liu J. J., Sharma K., Zangrandi L., Chen C., Humphrey S. J., Chiu Y.-T., Spetea M., Liu-Chen L.-Y., Schwarzer C., Mann M. In vivo brain GPCR signaling elucidated by phosphoproteomics. Science, 360:eaao4927 (2018). doi: 10.1126/science.aao492
Drieu la Rochelle A., Guillemyn K., Dumitrascuta M., Martin C., Utard V., Quillet R., Schneider S., Daubeuf F., Willemse T., Mampuys P., Maes B. U. W., Frossard N., Bihel F., Spetea M.,* Simonin F.,* Ballet S.* A bifunctional biased mu opioid agonist - neuropeptide FF receptor antagonist as analgesic with improved acute and chronic side effects. Pain 159:1705-1718 (2018). doi: 10.1097/j.pain.0000000000001262
Spetea M., Eans S. O., Ganno M. L., Lantero A., Mairegger M., Toll L., Schmidhammer H., McLaughlin J. P. Selective κ opioid receptor partial agonist HS666 produces potent antinociception without inducing aversion after i.c.v. administration in mice. Br. J. Pharmacol. 174:2444 -2456 (2017). doi: 10.1111/bph.13854
Erli F., Guerrieri E., Ben Haddou T., Lantero A., Mairegger M., Schmidhammer H., Spetea M. Highly potent and selective new diphenethylamines interacting with the κ-opioid receptor: Synthesis, pharmacology, and structure-activity relationships. J. Med. Chem. 60:579 -7590 (2017). doi: 10.1021/acs.jmedchem.7b00981
Dumitrascuta M., Ben Haddou T., Guerrieri E., Noha S. M., Schläfer L., Schmidhammer H., Spetea M. Synthesis, pharmacology and molecular modeling studies on 6-desoxo-N-methylmorphinans as potent µ-opioid receptor agonists. J. Med. Chem. 60:9407 -9412 (2017). doi: 10.1021/acs.jmedchem.7b01363
Noha M. S., Schmidhammer H., Spetea M. Molecular docking, molecular dynamics and structure-activity relationship explorations of 14-oxygenated N-methylmorphinan-6-ones as potent µ-opioid receptor agonists. ACS Chem. Neurosci. 8:1327-1337 (2017). doi: 10.1021/acschemneuro.6b00460
Kaserer T., Lantero A., Schmidhammer H., Spetea M., Schuster D. µ Opioid Receptor: Novel antagonists and structural modeling. Sci. Rep. 6:21548 (2016). doi:10.1038/srep21548