Guanidine Derivatives: How Simple Structural Modification of Histamine H(3)R Antagonists Has Led to the Discovery of Potent Muscarinic M(2)R/M(4)R Antagonists

[Image: see text] This article describes the discovery of novel potent muscarinic receptor antagonists identified during a search for more active histamine H(3) receptor (H(3)R) 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 H(3)R antagonists ADS1017 and ADS1020. These simple structural modifications of the histamine H(3)R 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.