Novel long‐acting antagonists of muscarinic ACh receptors

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F18%3A00490235" target="_blank" >RIV/67985823:_____/18:00490235 - isvavai.cz</a>

Výsledek na webu

<a href="http://dx.doi.org/10.1111/bph.14187" target="_blank" >http://dx.doi.org/10.1111/bph.14187</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1111/bph.14187" target="_blank" >10.1111/bph.14187</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Novel long‐acting antagonists of muscarinic ACh receptors

Popis výsledku v původním jazyce

The aim of this study was to develop potent and long-acting antagonists of muscarinic ACh receptors. The 4-hexyloxy and 4-butyloxy derivatives of 1-[2-(4-oxidobenzoyloxy)ethyl]-1,2,3,6-tetrahydropyridin-1-ium were synthesized and tested for biological activity. Antagonists with long-residence time at receptors are therapeutic targets for the treatment of several neurological and psychiatric human diseases. Their long-acting effects allow for reduced daily doses and adverse effects. The binding and antagonism of functional responses to the agonist carbachol mediated by 4-hexyloxy compounds were investigated in CHO cells expressing individual subtypes of muscarinic receptors and compared with 4-butyloxy analogues. The 4-hexyloxy derivatives were found to bind muscarinic receptors with micromolar affinity and antagonized the functional response to carbachol with a potency ranging from 30 nM at M-1 to 4 mu M at M-3 receptors. Under washing conditions to reverse antagonism, the half-life of their antagonistic action ranged from 1.7 h at M-2 to 5h at M-5 receptors. The 4-hexyloxy derivatives were found to be potent long-acting M-1-preferring antagonists. In view of current literature, M-1-selective antagonists may have therapeutic potential for striatal cholinergic dystonia, delaying epileptic seizure after organophosphate intoxication or relieving depression. These compounds may also serve as a tool for research into cognitive deficits.

Název v anglickém jazyce

Novel long‐acting antagonists of muscarinic ACh receptors

Popis výsledku anglicky

The aim of this study was to develop potent and long-acting antagonists of muscarinic ACh receptors. The 4-hexyloxy and 4-butyloxy derivatives of 1-[2-(4-oxidobenzoyloxy)ethyl]-1,2,3,6-tetrahydropyridin-1-ium were synthesized and tested for biological activity. Antagonists with long-residence time at receptors are therapeutic targets for the treatment of several neurological and psychiatric human diseases. Their long-acting effects allow for reduced daily doses and adverse effects. The binding and antagonism of functional responses to the agonist carbachol mediated by 4-hexyloxy compounds were investigated in CHO cells expressing individual subtypes of muscarinic receptors and compared with 4-butyloxy analogues. The 4-hexyloxy derivatives were found to bind muscarinic receptors with micromolar affinity and antagonized the functional response to carbachol with a potency ranging from 30 nM at M-1 to 4 mu M at M-3 receptors. Under washing conditions to reverse antagonism, the half-life of their antagonistic action ranged from 1.7 h at M-2 to 5h at M-5 receptors. The 4-hexyloxy derivatives were found to be potent long-acting M-1-preferring antagonists. In view of current literature, M-1-selective antagonists may have therapeutic potential for striatal cholinergic dystonia, delaying epileptic seizure after organophosphate intoxication or relieving depression. These compounds may also serve as a tool for research into cognitive deficits.

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

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

Rok uplatnění

2018

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

175

Číslo periodika v rámci svazku

10

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

13

Strana od-do

1731-1743

Kód UT WoS článku

000430658800012

EID výsledku v databázi Scopus

2-s2.0-85045208095