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.
- MeSH
- agonisté serotoninových receptorů farmakologie MeSH
- antagonisté serotoninu chemická syntéza farmakologie MeSH
- astrocyty účinky léků MeSH
- imidazoly chemická syntéza farmakologie MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- molekulární konformace MeSH
- neurity účinky léků MeSH
- neuroglie účinky léků MeSH
- neuroprotektivní látky chemická syntéza farmakologie MeSH
- poruchy učení chemicky indukované prevence a kontrola MeSH
- potkani Sprague-Dawley MeSH
- pyridiny chemická syntéza farmakologie MeSH
- receptory serotoninové účinky léků MeSH
- receptory spřažené s G-proteiny účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
