Dizocilpine derivatives as neuroprotective NMDA receptor antagonists without psychomimetic side effects

Result code in 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>

Alternative codes found

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

Result on the web

<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>

Result language

angličtina

Original language name

Dizocilpine derivatives as neuroprotective NMDA receptor antagonists without psychomimetic side effects

Original language description

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.

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30107 - Medicinal chemistry

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2024

Confidentiality

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

Name of the periodical

European Journal of Medicinal Chemistry

ISSN

0223-5234

e-ISSN

1768-3254

Volume of the periodical

280

Issue of the periodical within the volume

December

Country of publishing house

FR - FRANCE

Number of pages

18

Pages from-to

116981

UT code for WoS article

001343362800001

EID of the result in the Scopus database

2-s2.0-85206936917