From orexin receptor agonist YNT-185 to novel antagonists with drug-like properties for the treatment of insomnia

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00179906%3A_____%2F20%3A10417715" target="_blank" >RIV/00179906:_____/20:10417715 - isvavai.cz</a>

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=ZB~wxmU6OE" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=ZB~wxmU6OE</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bioorg.2020.104179" target="_blank" >10.1016/j.bioorg.2020.104179</a>

Jazyk výsledku

angličtina

Název v původním jazyce

From orexin receptor agonist YNT-185 to novel antagonists with drug-like properties for the treatment of insomnia

Popis výsledku v původním jazyce

YNT-185 is the first known small molecule acting as orexin 2 receptor (OX2R) agonist with implication to narcolepsy treatment, served as a template scaffold in generating a small set of seven compounds with predictive affinity to OX2R. The design of the new small molecules was driven mostly by improving physicochemical properties of the parent drug YNT-185 in parallel with in silico studies, later suggesting their favorable binding modes within the active site of OX2R. We obtained seven new potential OX2R binders that were evaluated in vitro for their CNS availability, cytotoxicity, and behavior pattern on OX2R. Out of them, 15 emerged as the most potent modulator of OX2R, which, contrary to YNT-185, displayed inverse mode of action, i.e. antagonist profile. 15 was also submitted to an in vivo experiment revealing its ability to permeate through BBB into the brain with a short half-life.

Název v anglickém jazyce

From orexin receptor agonist YNT-185 to novel antagonists with drug-like properties for the treatment of insomnia

Popis výsledku anglicky

YNT-185 is the first known small molecule acting as orexin 2 receptor (OX2R) agonist with implication to narcolepsy treatment, served as a template scaffold in generating a small set of seven compounds with predictive affinity to OX2R. The design of the new small molecules was driven mostly by improving physicochemical properties of the parent drug YNT-185 in parallel with in silico studies, later suggesting their favorable binding modes within the active site of OX2R. We obtained seven new potential OX2R binders that were evaluated in vitro for their CNS availability, cytotoxicity, and behavior pattern on OX2R. Out of them, 15 emerged as the most potent modulator of OX2R, which, contrary to YNT-185, displayed inverse mode of action, i.e. antagonist profile. 15 was also submitted to an in vivo experiment revealing its ability to permeate through BBB into the brain with a short half-life.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

<a href="/cs/project/GA17-08596S" target="_blank" >GA17-08596S: Nová účinná léčiva v terapii narkolepsie</a><br>

Návaznosti

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

Rok uplatnění

2020

Kód důvěrnosti údajů

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

Název periodika

Bioorganic Chemistry

ISSN

0045-2068

e-ISSN

—

Svazek periodika

103

Číslo periodika v rámci svazku

OCT

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

10

Strana od-do

104179

Kód UT WoS článku

000578958200010

EID výsledku v databázi Scopus

2-s2.0-85090052272