Chirality Matters: Fine-Tuning of Novel Monoamine Reuptake Inhibitors Selectivity through Manipulation of Stereochemistry.

Autor: Kalaba P; Department of Pharmaceutical Sciences, Faculty of Life Sciences, University of Vienna, 1090 Vienna, Austria., Pacher K; Department of Pharmaceutical Sciences, Faculty of Life Sciences, University of Vienna, 1090 Vienna, Austria., Neill PJ; Department of Pharmaceutical Sciences, Faculty of Life Sciences, University of Vienna, 1090 Vienna, Austria., Dragacevic V; Department of Pharmaceutical Sciences, Faculty of Life Sciences, University of Vienna, 1090 Vienna, Austria., Zehl M; Mass Spectrometry Centre, Faculty of Chemistry, University of Vienna, Währinger Straße 38, 1090 Vienna, Austria.; Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Währinger Straße 38, 1090 Vienna, Austria., Wackerlig J; Department of Pharmaceutical Sciences, Faculty of Life Sciences, University of Vienna, 1090 Vienna, Austria., Kirchhofer M; Department of Pharmaceutical Sciences, Faculty of Life Sciences, University of Vienna, 1090 Vienna, Austria., Sartori SB; Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), Leopold Franzens University Innsbruck, 6020 Innsbruck, Austria., Gstach H; Department of Pharmaceutical Sciences, Faculty of Life Sciences, University of Vienna, 1090 Vienna, Austria., Kouhnavardi S; Department of Pharmaceutical Sciences, Faculty of Life Sciences, University of Vienna, 1090 Vienna, Austria., Fabisikova A; Mass Spectrometry Centre, Faculty of Chemistry, University of Vienna, Währinger Straße 38, 1090 Vienna, Austria., Pillwein M; Department of Pharmaceutical Sciences, Faculty of Life Sciences, University of Vienna, 1090 Vienna, Austria., Monje-Quiroga F; Center for Physiology and Pharmacology, Department of Neurophysiology and Neuropharmacology, Medical University of Vienna, 1090 Vienna, Austria., Ebner K; Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), Leopold Franzens University Innsbruck, 6020 Innsbruck, Austria., Prado-Roller A; X-ray Structure Analysis Centre, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria., Singewald N; Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), Leopold Franzens University Innsbruck, 6020 Innsbruck, Austria., Urban E; Department of Pharmaceutical Sciences, Faculty of Life Sciences, University of Vienna, 1090 Vienna, Austria., Langer T; Department of Pharmaceutical Sciences, Faculty of Life Sciences, University of Vienna, 1090 Vienna, Austria., Pifl C; Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria., Lubec J; Programme for Proteomics, Paracelsus Medical University, 5020 Salzburg, Austria., Leban JJ; Programme for Proteomics, Paracelsus Medical University, 5020 Salzburg, Austria., Lubec G; Programme for Proteomics, Paracelsus Medical University, 5020 Salzburg, Austria.
Jazyk: angličtina
Zdroj: Biomolecules [Biomolecules] 2023 Sep 19; Vol. 13 (9). Date of Electronic Publication: 2023 Sep 19.
DOI: 10.3390/biom13091415
Abstrakt: The high structural similarity, especially in transmembrane regions, of dopamine, norepinephrine, and serotonin transporters, as well as the lack of all crystal structures of human isoforms, make the specific targeting of individual transporters rather challenging. Ligand design itself is also rather limited, as many chemists, fully aware of the synthetic and analytical challenges, tend to modify lead compounds in a way that reduces the number of chiral centers and hence limits the potential chemical space of synthetic ligands. We have previously shown that increasing molecular complexity by introducing additional chiral centers ultimately leads to more selective and potent dopamine reuptake inhibitors. Herein, we significantly extend our structure-activity relationship of dopamine transporter-selective ligands and further demonstrate how stereoisomers of defined absolute configuration may fine-tune and direct the activity towards distinct targets. From the pool of active compounds, using the examples of stereoisomers 7h and 8h , we further showcase how in vitro activity significantly differs in in vivo drug efficacy experiments, calling for proper validation of individual stereoisomers in animal studies. Furthermore, by generating a large library of compounds with defined absolute configurations, we lay the groundwork for computational chemists to further optimize and rationally design specific monoamine transporter reuptake inhibitors.
Databáze: MEDLINE
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