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

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

Biomolecules (2023-09-28)
Predrag Kalaba, Katharina Pacher, Philip John Neill, Vladimir Dragacevic, Martin Zehl, Judith Wackerlig, Michael Kirchhofer, Simone B Sartori, Hubert Gstach, Shima Kouhnavardi, Anna Fabisikova, Matthias Pillwein, Francisco Monje-Quiroga, Karl Ebner, Alexander Prado-Roller, Nicolas Singewald, Ernst Urban, Thierry Langer, Christian Pifl, Jana Lubec, Johann Jakob Leban, Gert Lubec
摘要

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.

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抗βIII微管蛋白抗体,Alexa Fluor 488偶联物 | AB15708A4, from rabbit, ALEXA FLUOR 488