Novel Histamine H3-Receptor Antagonists with Benzyl Ether Structure or Related Moieties: Synthesis and Structure-Activity Relationships

In search of new histamine H 3 -receptor ligands sixteen ether derivatives of 3-(1H-imidazol-4-yl)propanol with benzylic partial structure or related moieties were prepared and investigated as H 3 -receptor antagonists. The new compounds belong to a general construction pattern developed by other histamine H 3 -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 H 3 -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 ED 50 or 3.2 ± 1.9 mg/kg regarding enhancement of endogenous histamine in brain after p.o. administration to mice. Furthermore, comparison of the H 3 -receptor activities measured on synaptosomes of rat cerebral cortex and on guinea pig ileum gave a good correlation indicating homogeneity of central and peripheral H 3 -receptor test models. The most interesting compounds were also evaluated in functional in vitro assays with regard to their activities at histamine H 1 -, H 2 -, and muscarinic M 3 -receptors. The tested compounds showed very weak activities at these receptor subtypes demonstrating their H 3 -receptor selectivity.