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

Result code in 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>
Result on the web
<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>

Result language
angličtina
Original language name
Guanidine Derivatives: How Simple Structural Modification of Histamine H3R Antagonists Has Led to the Discovery of Potent Muscarinic M2R/M4R Antagonists
Original language description
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.
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30105 - Physiology (including cytology)

Project
<a href="/en/project/GA19-05318S" target="_blank" >GA19-05318S: Molecular mechanisms of allosteric modulation of muscarinic acetylcholine receptors by neurosteroids and cholesterol</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year
2021
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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