Novel M-2-selective, G(i)-biased agonists of muscarinic acetylcholine receptors

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F20%3A00524282" target="_blank" >RIV/67985823:_____/20:00524282 - isvavai.cz</a>

Výsledek na webu

<a href="https://doi.org/10.1111/bph.14970" target="_blank" >https://doi.org/10.1111/bph.14970</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1111/bph.14970" target="_blank" >10.1111/bph.14970</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Novel M-2-selective, G(i)-biased agonists of muscarinic acetylcholine receptors

Popis výsledku v původním jazyce

More than 30% of currently marketed medications act via GPCRs. Thus, GPCRs represent one of the most important pharmacotherapeutic targets. In contrast to traditional agonists activating multiple signalling pathways, agonists activating a single signalling pathway represent a new generation of drugs with increased specificity and fewer adverse effects. Two of the tested new compounds only inhibited cAMP synthesis in CHO cells, primary cultures, and native tissues, with selectivity for M2 muscarinic receptors and displaying bias towards the Gi signalling pathway at all subtypes of muscarinic receptors. Molecular modelling revealed interactions with the orthosteric binding site in a way specific for a given agonist followed by agonist-specific changes in the conformation of the receptor. The identified compounds may serve as lead structures in the search for novel non-steroidal and non-opioid analgesics acting via M2 and M4 muscarinic receptors with reduced side effects associated with activation of the phospholipase C signalling pathway.

Název v anglickém jazyce

Novel M-2-selective, G(i)-biased agonists of muscarinic acetylcholine receptors

Popis výsledku anglicky

More than 30% of currently marketed medications act via GPCRs. Thus, GPCRs represent one of the most important pharmacotherapeutic targets. In contrast to traditional agonists activating multiple signalling pathways, agonists activating a single signalling pathway represent a new generation of drugs with increased specificity and fewer adverse effects. Two of the tested new compounds only inhibited cAMP synthesis in CHO cells, primary cultures, and native tissues, with selectivity for M2 muscarinic receptors and displaying bias towards the Gi signalling pathway at all subtypes of muscarinic receptors. Molecular modelling revealed interactions with the orthosteric binding site in a way specific for a given agonist followed by agonist-specific changes in the conformation of the receptor. The identified compounds may serve as lead structures in the search for novel non-steroidal and non-opioid analgesics acting via M2 and M4 muscarinic receptors with reduced side effects associated with activation of the phospholipase C signalling pathway.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30105 - Physiology (including cytology)

Projekt

<a href="/cs/project/GA17-16182S" target="_blank" >GA17-16182S: Molekulární základy funkční selektivity solí N-subtituovaného tetrahydropyridinia na muskarinových receptorech</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2020

Kód důvěrnosti údajů

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

Název periodika

British Journal of Pharmacology

ISSN

0007-1188

e-ISSN

—

Svazek periodika

177

Číslo periodika v rámci svazku

9

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

17

Strana od-do

2073-2089

Kód UT WoS článku

000513355700001

EID výsledku v databázi Scopus

2-s2.0-85079457609