Imidazopyridine-based 5-HT6 receptor neutral antagonists: impact of N1-benzyl and N1-phenylsulfonyl fragments on different receptor conformational state

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F21%3A73608269" target="_blank" >RIV/61989592:15310/21:73608269 - isvavai.cz</a>
Result on the web
<a href="https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.0c02009" target="_blank" >https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.0c02009</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acs.jmedchem.0c02009" target="_blank" >10.1021/acs.jmedchem.0c02009</a>

Result language
angličtina
Original language name
Imidazopyridine-based 5-HT6 receptor neutral antagonists: impact of N1-benzyl and N1-phenylsulfonyl fragments on different receptor conformational state
Original language description
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-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-OHDA- 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 NOR test in rats. We propose 7e as a probe for further understanding of the functional outcomes of different states of the 5-HT6R.
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
10401 - Organic chemistry

Project
<a href="/en/project/NV17-31834A" target="_blank" >NV17-31834A: Targeting BCR signalosome in B-cell malignancies</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year
2021
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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