Synthesis and Structure-Activity Relationships of Cyanoguanidine-Type and Structurally Related Histamine H4 Receptor Agonists

Recently, we identified high-affinity human histamine H-3 (hH(3)R) and H-4 receptor (hH(4)R) ligands among a series of N-G-acylated imidazolylpropylguanidines, which were originally designed as histamine H-2 receptor (H2R) agonists. Aiming at selectivity for hH(4)R, the acylguanidine group was replaced with related moieties. Within a series of cyanoguanidines, 2-cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[(2-phenylthio)ethyl]guanidine (UR-PI376, 67) was identified as the most potent hH(4)R agonist (pEC(50) = 7.47, alpha = 0.93) showing negligible hH(1)R and hH(2)R activities and significant selectivity over the hH(3)R (pK(B) = 6.00, alpha = -0.28), as determined in steady-state GTPase assays using. membrane preparations of hH(x)R-expressing Sf9 cells. In contrast to previously described selective H4R agonists, this compound and other 3-substituted derivatives are devoid of agonistic activity at the other HR subtypes. Modeling of the binding mode of 67 suggests that the cyanoguanidine moiety forms charge-assisted hydrogen bonds not only with the conserved Asp-94 but also with the hH(4)R-specific Arg-341 residue. 2-Carbamoyl-1-[2-(1H-imidazol-4-yl)ethyl]-3-(3-phenylpropyl)guanidine (UR-PI97, 88) was unexpectedly identified as a highly potent and selective hH(3)R inverse agonist (pK(B) = 8.42, > 300-fold selectivity over the other HR subtypes).