Balancing rigidity and flexibility: Optimised 4-(hexyloxy)benzoate antagonists with enhanced affinity and tuneable duration at muscarinic receptors

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F25%3A00642797" target="_blank" >RIV/67985823:_____/25:00642797 - isvavai.cz</a>

Výsledek na webu

<a href="https://doi.org/10.1016/j.biopha.2025.118653" target="_blank" >https://doi.org/10.1016/j.biopha.2025.118653</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.biopha.2025.118653" target="_blank" >10.1016/j.biopha.2025.118653</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Balancing rigidity and flexibility: Optimised 4-(hexyloxy)benzoate antagonists with enhanced affinity and tuneable duration at muscarinic receptors

Popis výsledku v původním jazyce

Muscarinic acetylcholine receptors (mAChRs) are key regulators of diverse physiological processes and longstanding therapeutic targets. Building on the long-acting antagonist KH-5, we synthesised and evaluated a series of 4-(hexyloxy)benzoate derivatives and their quaternary N-methylated analogues to explore how structural modifications influence receptor affinity and the duration of functional antagonism. Our structure-activity analysis revealed that introducing a rigid azabicyclo[2.2.2]octan-1-ium group boosted binding affinity (up to 250-fold compared to parental compounds) yet reduced the half-life of functional antagonism. In contrast, analogues with moderate flexibility maintained high potency while preserving longer receptor residence time. Computational docking and molecular dynamics (MD) simulations demonstrated that stable hydrogen bonding with residue N6.52 and salt-bridge formation with D3.32 were critical for sustained ligand binding to the receptor, with MD-derived metrics outperforming docking energies in predicting biological activity. Crucially, a positively charged nitrogen and a 4-hexyloxy substituent are essential features for high-affinity binding and prolonged antagonism. Shortening the alkyl chain resulted in a marked loss of affinity and abolished sustained activity. These findings underscore the need to balance molecular rigidity with conformational flexibility and charge distribution in the design of long-residence mAChR antagonists, offering a framework for further development of mAChR-targeted long-acting antagonists.

Název v anglickém jazyce

Balancing rigidity and flexibility: Optimised 4-(hexyloxy)benzoate antagonists with enhanced affinity and tuneable duration at muscarinic receptors

Popis výsledku anglicky

Muscarinic acetylcholine receptors (mAChRs) are key regulators of diverse physiological processes and longstanding therapeutic targets. Building on the long-acting antagonist KH-5, we synthesised and evaluated a series of 4-(hexyloxy)benzoate derivatives and their quaternary N-methylated analogues to explore how structural modifications influence receptor affinity and the duration of functional antagonism. Our structure-activity analysis revealed that introducing a rigid azabicyclo[2.2.2]octan-1-ium group boosted binding affinity (up to 250-fold compared to parental compounds) yet reduced the half-life of functional antagonism. In contrast, analogues with moderate flexibility maintained high potency while preserving longer receptor residence time. Computational docking and molecular dynamics (MD) simulations demonstrated that stable hydrogen bonding with residue N6.52 and salt-bridge formation with D3.32 were critical for sustained ligand binding to the receptor, with MD-derived metrics outperforming docking energies in predicting biological activity. Crucially, a positively charged nitrogen and a 4-hexyloxy substituent are essential features for high-affinity binding and prolonged antagonism. Shortening the alkyl chain resulted in a marked loss of affinity and abolished sustained activity. These findings underscore the need to balance molecular rigidity with conformational flexibility and charge distribution in the design of long-residence mAChR antagonists, offering a framework for further development of mAChR-targeted long-acting antagonists.

Druh

J_SC - Článek v periodiku v databázi SCOPUS

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

<a href="/cs/project/GA23-04670S" target="_blank" >GA23-04670S: Vývoj nových dlouhodobě působících antagonistů muskarinových receptorů na základě jejich strukturních vlastností</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

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

Název periodika

Biomedicine & Pharmacotherapy

ISSN

0753-3322

e-ISSN

1950-6007

Svazek periodika

192

Číslo periodika v rámci svazku

Nov

Stát vydavatele periodika

FR - Francouzská republika

Počet stran výsledku

20

Strana od-do

118653

Kód UT WoS článku

—

EID výsledku v databázi Scopus

2-s2.0-105020581430