NOVEL HISTAMINE H-3 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 derivati ves of 3-(1H-imidazol-4-yl)propanol with benzylic partial structure or related moieties were prepared and investigated as H-3-receptor antag onists. The new compounds belong to a general construction pattern dev eloped by other histamine H-3-receptor antagonists. Structural modific ations were introduced in an attempt to optimize in vitro as well as i n 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 com pounds with bulky lipophilic residues were also active under in vivo c onditions. The most active compound within this series was 3-(1H-imida zol-4-yl)propyl 1-naphthylmethyl ether (4n) presenting an ED(50) of 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 a nd on guinea pig ileum gave a good correlation indicating homogeneity of central and peripheral H-3-receptor test models. The most interesti ng compounds were also evaluated in functional in vitro assays with re gard to their activities at histamine H-1-, H-2-, and muscarinic M(3)- receptors. The tested compounds showed very weak activities at these r eceptor subtypes demonstrating their H-3-receptor selectivity.