Guanidine Derivatives: How Simple Structural Modification
of Histamine H3R Antagonists Has Led to the Discovery of
Potent Muscarinic M2R/M4R Antagonists
posted on 2021-06-08, 16:04authored byMarek Staszewski, Dominik Nelic, Jakub Jończyk, Mariam Dubiel, Annika Frank, Holger Stark, Marek Bajda, Jan Jakubik, Krzysztof Walczyński
This article describes
the discovery of novel potent muscarinic
receptor antagonists identified during a search for more active histamine
H3 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 M2 and M4 receptors
(hM2R and hM4R, 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 hM2R and hM4R were 2.8 nM and 5.1 nM, respectively.