SEARCH FOR NOVEL LEADS FOR HISTAMINE H-3 RECEPTOR ANTAGONISTS - OXYGEN-CONTAINING DERIVATIVES

This study was performed in order to develop new leads for antagonists of the histamine H-3-receptor subtype. omega-(1 H-Imidazol-4-yl)alkyl derivatives with ester, ketone or alcohol functionality in the side c hain were synthesized and tested concerning their H-3-receptor antagon ist activity on synaptosomes of rat cerebral cortex. The novel compoun ds, which possess no nitrogen-containing polar group in the side chain of the imidazole moiety, presented moderate to high antagonist potenc y in vitro. In this series 3-(1 H-imidazol-4-yl)propyl-3-cyclopentylpr opanoate (4) was the most potent compound in vitro with -log K-i = 8.5 . Unfortunately, no central antagonist Hs-receptor activity was detect able for ester derivatives in the in vitro H-3-receptor assay based up on measurement of brain N-tau-methylhistamine levels after p.o. admini stration to mice. Some of these novel antagonists are useful tools for investigations on ligand-receptor interaction because of their distin ct receptor activities. On the other hand, the ketone derivative 1-(1 H-imidazol-4-yl)-7-phenyl-4-heptanone (9) in vitro presented an ED50-v alue of 3.5 +/- 1.5 mg/kg p.o. thus proving to be a new lead for furth er drug investigations. The most potent compounds in vitro and in vivo also showed high H-3-receptor selectivity when tested at other histam ine receptor subtypes.