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/)



Recent references

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

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