NOVEL CARBAMATES AS POTENT HISTAMINE H-3 RECEPTOR ANTAGONISTS WITH HIGH IN-VITRO AND ORAL IN-VIVO ACTIVITY

The known histamine H-3 receptor antagonists burimamide, thioperamide, clobenpropit, and a related homohistamine thioamide derivative were t aken as templates in search for new leads. Novel histamine H-3 recepto r antagonists structurally described as carbamate derivatives of 3-(1H -imidazol-4-yl)propanol were prepared in high yields by treatment of t he alcohol with corresponding isocyanates or carbamoyl chlorides and i nvestigated for their H-3 receptor antagonist activity. Different chai n lengths and various substituents possessing different electronic and steric parameters were introduced and structure-activity relationship s established. In different functional tests, the new antagonists show ed high Hs receptor antagonist potencies in, vitro (-log K-i values of 6.4-8.4) at synaptosomes of rat cerebral cortex and low activities at histamine H-1 and H-2 receptor subtypes. They were also screened for their central in vivo activity in mice after peroral administration. T he most promising compounds (2, 16, 19) showed ED(50) values of about 1-2 mg/kg and thus are potential drugs for the therapy of Hg receptor dependent diseases. Some of the novel carbamate derivatives are H-3 re ceptor selective compounds with high in vitro and in vivo activity.