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.

Department of Neurochemistry Institute of Physiology CAS Videnska 1083 CZ142 20 Prague Czech Republic

Department of Physicochemical Drug Analysis Faculty of Pharmacy Jagiellonian University Medical College Medyczna 9 30 688 Kraków Poland

Department of Synthesis and Technology of Drugs Medical University of Lodz ul Muszyńskiego 1 90 151 Łódź Poland

Institute of Pharmaceutical and Medicinal Chemistry Heinrich Heine University Düsseldorf Universitaetsstr 1 Duesseldorf 40225 Germany

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Multitargeting nature of muscarinic orthosteric agonists and antagonists