Dizocilpine derivatives as neuroprotective NMDA receptor antagonists without psychomimetic side effects

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378041%3A_____%2F24%3A00599831" target="_blank" >RIV/68378041:_____/24:00599831 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/60162694:G44__/25:00563897 RIV/00179906:_____/24:10488968 RIV/00023752:_____/24:43921383

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0223523424008638?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0223523424008638?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejmech.2024.116981" target="_blank" >10.1016/j.ejmech.2024.116981</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Dizocilpine derivatives as neuroprotective NMDA receptor antagonists without psychomimetic side effects

Popis výsledku v původním jazyce

We aimed to prepare novel dibenzo [a,d][7]annulen derivatives that act on N-methyl-D-aspartate (NMDA) receptors with potential neuroprotective effects. Our approach involved modifying the tropane moiety of MK-801, a potent open-channel blocker known for its psychomimetic side effects, by introducing a seven-membered ring with substituted base moieties specifically to alleviate these undesirable effects. Our in silico analyses showed that these derivatives should have high gastrointestinal absorption and cross the blood-brain barrier (BBB). Our pharmacokinetic studies in rats supported this conclusion and confirmed the ability of leading compounds 3l and 6f to penetrate the BBB. Electrophysiological experiments showed that all compounds exhibited different inhibitory activity towards the two major NMDA receptor subtypes, GluN1/GluN2A and GluN1/GluN2B. Of the selected compounds intentionally differing in the inhibitory efficacy, 6f showed high relative inhibition (~90 % for GluN1/GluN2A), while 3l showed moderate inhibition (~50 %). An in vivo toxicity study determined that compounds 3l and 6f were safe at 10 mg/kg doses with no adverse effects. Behavioral studies demonstrated that these compounds did not induce hyperlocomotion or impair prepulse inhibition of startle response in rats. Neuroprotective assays using a model of NMDA-induced hippocampal neurodegeneration showed that compoundn3l at a concentration of 30 μM significantly reduced hippocampal damage in rats. These results suggest that these novel dibenzo [a,d][7]annulen derivatives are promising candidates for developing NMDA receptortargeted therapies with minimal psychotomimetic side effects.

Název v anglickém jazyce

Dizocilpine derivatives as neuroprotective NMDA receptor antagonists without psychomimetic side effects

Popis výsledku anglicky

We aimed to prepare novel dibenzo [a,d][7]annulen derivatives that act on N-methyl-D-aspartate (NMDA) receptors with potential neuroprotective effects. Our approach involved modifying the tropane moiety of MK-801, a potent open-channel blocker known for its psychomimetic side effects, by introducing a seven-membered ring with substituted base moieties specifically to alleviate these undesirable effects. Our in silico analyses showed that these derivatives should have high gastrointestinal absorption and cross the blood-brain barrier (BBB). Our pharmacokinetic studies in rats supported this conclusion and confirmed the ability of leading compounds 3l and 6f to penetrate the BBB. Electrophysiological experiments showed that all compounds exhibited different inhibitory activity towards the two major NMDA receptor subtypes, GluN1/GluN2A and GluN1/GluN2B. Of the selected compounds intentionally differing in the inhibitory efficacy, 6f showed high relative inhibition (~90 % for GluN1/GluN2A), while 3l showed moderate inhibition (~50 %). An in vivo toxicity study determined that compounds 3l and 6f were safe at 10 mg/kg doses with no adverse effects. Behavioral studies demonstrated that these compounds did not induce hyperlocomotion or impair prepulse inhibition of startle response in rats. Neuroprotective assays using a model of NMDA-induced hippocampal neurodegeneration showed that compoundn3l at a concentration of 30 μM significantly reduced hippocampal damage in rats. These results suggest that these novel dibenzo [a,d][7]annulen derivatives are promising candidates for developing NMDA receptortargeted therapies with minimal psychotomimetic side effects.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30107 - Medicinal chemistry

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

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

Název periodika

European Journal of Medicinal Chemistry

ISSN

0223-5234

e-ISSN

1768-3254

Svazek periodika

280

Číslo periodika v rámci svazku

December

Stát vydavatele periodika

FR - Francouzská republika

Počet stran výsledku

18

Strana od-do

116981

Kód UT WoS článku

001343362800001

EID výsledku v databázi Scopus

2-s2.0-85206936917