Synthesis of metabolically stable and biologically active modulators of NMDA receptors

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00645835" target="_blank" >RIV/61388963:_____/25:00645835 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/67985823:_____/25:00645835

Výsledek na webu

<a href="https://hdl.handle.net/11104/0375621" target="_blank" >https://hdl.handle.net/11104/0375621</a>

DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Synthesis of metabolically stable and biologically active modulators of NMDA receptors

Popis výsledku v původním jazyce

The poster presents the design, synthesis and pharmacological characterization of metabolically stable steroidal modulators of N methyl D aspartate receptors (NMDARs) based on a pregnenolone scaffold functionalized as C 20 oxime ethers. A modular synthetic route was optimized so that the oxime derivatization is introduced in the final step, enabling rapid preparation of focused libraries with systematically varied carboxylic acid chain length and terminal functionalities. Whole cell patch clamp recordings at GluN1/GluN2B receptors revealed that many oxime analogues act as positive allosteric modulators, with selected C 20 derivatives displaying higher efficacy and potency than the parent hit and the endogenous neurosteroid pregnenolone sulfate. The study further demonstrates high stability of these oximes in rat plasma, reduced stability for long chain ketone analogues in microsomes, and documents that several compounds combine NMDAR potentiation with favorable kinetic and thermodynamic solubility profiles, nominating lead structures for in vivo evaluation in models of glutamatergic dysfunction.

Název v anglickém jazyce

Synthesis of metabolically stable and biologically active modulators of NMDA receptors

Popis výsledku anglicky

The poster presents the design, synthesis and pharmacological characterization of metabolically stable steroidal modulators of N methyl D aspartate receptors (NMDARs) based on a pregnenolone scaffold functionalized as C 20 oxime ethers. A modular synthetic route was optimized so that the oxime derivatization is introduced in the final step, enabling rapid preparation of focused libraries with systematically varied carboxylic acid chain length and terminal functionalities. Whole cell patch clamp recordings at GluN1/GluN2B receptors revealed that many oxime analogues act as positive allosteric modulators, with selected C 20 derivatives displaying higher efficacy and potency than the parent hit and the endogenous neurosteroid pregnenolone sulfate. The study further demonstrates high stability of these oximes in rat plasma, reduced stability for long chain ketone analogues in microsomes, and documents that several compounds combine NMDAR potentiation with favorable kinetic and thermodynamic solubility profiles, nominating lead structures for in vivo evaluation in models of glutamatergic dysfunction.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

10401 - Organic chemistry

Projekt

<a href="/cs/project/TN02000109" target="_blank" >TN02000109: Personalizovaná medicína: Translačním výzkumem k biomedicínským aplikacím</a><br>

Návaznosti

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

Rok uplatnění

2025

Kód důvěrnosti údajů

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