Effect of hexyloxy position on antagonistic properties of KH-5 (1-{2-[4-(hexyloxy)benzoyloxy]ethyl}-1-methyl-1,2,3,6-tetrahydropyridin-1-ium iodide) at muscarinic acetylcholine receptors

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F25%3A00644690" target="_blank" >RIV/67985823:_____/25:00644690 - isvavai.cz</a>

Result on the web

<a href="http://10.1016/j.biopha.2025.117977" target="_blank" >http://10.1016/j.biopha.2025.117977</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.biopha.2025.117977" target="_blank" >10.1016/j.biopha.2025.117977</a>

Result language

angličtina

Original language name

Effect of hexyloxy position on antagonistic properties of KH-5 (1-{2-[4-(hexyloxy)benzoyloxy]ethyl}-1-methyl-1,2,3,6-tetrahydropyridin-1-ium iodide) at muscarinic acetylcholine receptors

Original language description

Antagonists with a long residence time at the receptors are desired for the possibility of reducing daily doses and side effects. KH-5 (1-{2-[4-(hexyloxy)benzoyloxy]ethyl}-1-methyl-1,2,3,6-tetrahydropyridin-1-ium iodide) is the long-acting M1-preferring bitopic muscarinic antagonist with a half-life at muscarinic receptors of up to five hours. The binding of 2-hexyloxy and 3-hexyloxy analogues of KH-5 was simulated in silico, compounds were synthesized and their binding and antagonistic properties were measured experimentally in CHO cells expressing individual subtypes of muscarinic acetylcholine receptors. The overall binding affinities of the new compounds were similar to their respective parent compounds. Shifting the hexyloxy chain to ortho and meta positions led to a decrease in potency at the M1 receptor but an increase in potency at the M2 receptor and abolition of long-term antagonism. Preservation of the para position of the hexyloxy chain is essential for the further development of M1-preferring antagonists. Modifications of the basic centre may be the way to improve the geometry of antagonists towards long residence times to obtain the desired long-acting muscarinic antagonists in the future. The additional challenge for further development is the low metabolic stability of compounds.

Czech name

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Czech description

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Type

J_SC - Article in a specialist periodical, which is included in the SCOPUS database

CEP classification

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OECD FORD branch

30104 - Pharmacology and pharmacy

Project

<a href="/en/project/GA23-04670S" target="_blank" >GA23-04670S: Structure-activity guided design of novel long-acting antagonists of muscarinic receptors</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2025

Confidentiality

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

Name of the periodical

Biomedicine & Pharmacotherapy

ISSN

0753-3322

e-ISSN

1950-6007

Volume of the periodical

185

Issue of the periodical within the volume

April

Country of publishing house

FR - FRANCE

Number of pages

15

Pages from-to

117977

UT code for WoS article

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EID of the result in the Scopus database

2-s2.0-86000768670