Guanidine Derivatives: How Simple Structural Modification of Histamine H3R Antagonists Has Led to the Discovery of Potent Muscarinic M2R/M4R Antagonists

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F21%3A00544565" target="_blank" >RIV/67985823:_____/21:00544565 - isvavai.cz</a>

Výsledek na webu

<a href="https://pubs.acs.org/doi/10.1021/acschemneuro.1c00237" target="_blank" >https://pubs.acs.org/doi/10.1021/acschemneuro.1c00237</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acschemneuro.1c00237" target="_blank" >10.1021/acschemneuro.1c00237</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Guanidine Derivatives: How Simple Structural Modification of Histamine H3R Antagonists Has Led to the Discovery of Potent Muscarinic M2R/M4R Antagonists

Popis výsledku v původním jazyce

This article describes the discovery of novel potent muscarinic receptor antagonists identified during a search for more active histamine H-3 receptor (H3R) ligands. The idea was to replace the flexible seven methylene linker with a semirigid 1,4-cyclohexylene or p-phenylene substituted group of the previously described histamine H3R antagonists ADS1017 and ADS1020. These simple structural modifications of the histamine H3R antagonist led to the emergence of additional pharmacological effects, some of which unexpectedly showed strong antagonist potency at muscarinic receptors. This paper reports the routes of synthesis and pharmacological characterization of guanidine derivatives, a novel chemotype of muscarinic receptor antagonists binding to the human muscarinic M-2 and M-4 receptors (hM(2)R and hM(4)R, respectively) in nanomolar concentration ranges. The affinities of the newly synthesized ADS10227 (1-{4-{4-{[4-(phenoxymethyl)cyclohexyl]methyl}piperazin-1-yl} but-1-yl}-1-(benzyl)guanidine) at hM(2)R and hM(4)R were 2.8 nM and 5.1 nM, respectively.

Název v anglickém jazyce

Guanidine Derivatives: How Simple Structural Modification of Histamine H3R Antagonists Has Led to the Discovery of Potent Muscarinic M2R/M4R Antagonists

Popis výsledku anglicky

This article describes the discovery of novel potent muscarinic receptor antagonists identified during a search for more active histamine H-3 receptor (H3R) ligands. The idea was to replace the flexible seven methylene linker with a semirigid 1,4-cyclohexylene or p-phenylene substituted group of the previously described histamine H3R antagonists ADS1017 and ADS1020. These simple structural modifications of the histamine H3R antagonist led to the emergence of additional pharmacological effects, some of which unexpectedly showed strong antagonist potency at muscarinic receptors. This paper reports the routes of synthesis and pharmacological characterization of guanidine derivatives, a novel chemotype of muscarinic receptor antagonists binding to the human muscarinic M-2 and M-4 receptors (hM(2)R and hM(4)R, respectively) in nanomolar concentration ranges. The affinities of the newly synthesized ADS10227 (1-{4-{4-{[4-(phenoxymethyl)cyclohexyl]methyl}piperazin-1-yl} but-1-yl}-1-(benzyl)guanidine) at hM(2)R and hM(4)R were 2.8 nM and 5.1 nM, respectively.

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/GA19-05318S" target="_blank" >GA19-05318S: Molekulární mechanismy alosterické modulace muskarinových receptorů pro acetylcholin neurosteroidy a cholesterolem</a><br>

Návaznosti

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

Rok uplatnění

2021

Kód důvěrnosti údajů

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

Název periodika

ACS Chemical Neuroscience

ISSN

1948-7193

e-ISSN

1948-7193

Svazek periodika

12

Číslo periodika v rámci svazku

13

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

17

Strana od-do

2503-2519

Kód UT WoS článku

000672585800021

EID výsledku v databázi Scopus

2-s2.0-85108650200