G-protein coupled receptors (GPCRs) exist in an equilibrium of multiple conformational states, including different active states, which depend on the nature of the bound ligand. In consequence, different conformational states can initiate specific signal transduction pathways. The study identified compound 7e, which acts as a potent 5-hydroxytryptamine type 6 receptor (5-HT6R) neutral antagonist at Gs and does not impact neurite growth (process controlled by Cdk5). MD simulations highlighted receptor conformational changes for 7e and inverse agonist PZ-1444. In cell-based assays, neutral antagonists of the 5-HT6R (7e and CPPQ), but not inverse agonists (SB-258585, intepirdine, PZ-1444), displayed glioprotective properties against 6-hydroxydopamine-induced and doxorubicin-induced cytotoxicity. These suggest that targeting the activated conformational state of the 5-HT6R with neutral antagonists implicates the protecting properties of astrocytes. Additionally, 7e prevented scopolamine-induced learning deficits in the novel object recognition test in rats. We propose 7e as a probe for further understanding of the functional outcomes of different states of the 5-HT6R.

Faculty of Pharmacy Department of Organic Chemistry Jagiellonian University Medical College 9 Medyczna Street Kraków 30 688 Poland

Faculty of Pharmacy Jagiellonian University Medical College 9 Medyczna Street Kraków 30 688 Poland

Faculty of Science Department of Organic Chemistry Palacký University 17 listopadu 12 Olomouc 771 46 Czech Republic

Institut de Génomique Fonctionnelle Univ Montpellier INSERM CNRS 141 Rue de la Cardonille Montpellier 34 094 France

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacký University Hněvotínská 5 Olomouc 779 00 Czech Republic

Maj Institute of Pharmacology Polish Academy of Sciences 12 Smętna Street Kraków 31 343 Poland

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