In search of new histamine H3-receptor ligands sixteen ether derivatives of 3-(1H-imidazol-4-yl)propanol with benzylic partial structure or related moieties were prepared and investigated as H3-receptor antagonists. The new compounds belong to a general construction pattern developed by other histamine H3-receptor antagonists. Structural modifications were introduced in an attempt to optimize in vitro as well as in vivo activity. Structure-activity relationships of the new histamine H3-receptor antagonists are discussed. All ether derivatives showed in vitro activities in the nanomolar concentration range, but only compounds with bulky lipophilic residues were also active under in vivo conditions. The most active compound within this series was 3-(1H-imidazol-4-yl)propyl 1-naphthylmethyl ether (4n) presenting an ED50 of 3.2 +/- 1.9 mg/kg regarding enhancement of endogenous histamine in brain after p.o. administration to mice. Furthermore, comparison of the H3-receptor activities measured on synaptosomes of rat cerebral cortex and on guinea pig ileum gave a good correlation indicating homogeneity of central and peripheral H3-receptor test models. The most interesting compounds were also evaluated in functional in vitro assays with regard to their activities at histamine H1-, H2-, and muscarinic M3-receptors. The tested compounds showed very weak activities at these receptor subtypes demonstrating their H3-receptor selectivity.