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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10401 - Organic chemistry

Projekt

<a href="/cs/project/NV17-31834A" target="_blank" >NV17-31834A: Inhibice BCR signalosomu u B buněčných malignit</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

JOURNAL OF MEDICINAL CHEMISTRY

ISSN

0022-2623

e-ISSN

—

Svazek periodika

64

Číslo periodika v rámci svazku

2

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

17

Strana od-do

1180-1196

Kód UT WoS článku

000614306000018

EID výsledku v databázi Scopus

2-s2.0-85099825660