Development of chiral N-alkylcarbamates as new leads for potent and selective H-3-receptor antagonists: Synthesis, capillary electrophoresis, and in vitro and oral in vivo activity

Novel carbamates as derivatives of 3-(1H-imidazol-4-yl)propanol with an N-a lkyl chain were prepared as histamine H-3-receptor antagonists. Branching o f the N-alkyl side chain with methyl groups led to chiral compounds which w ere synthesized stereospecifically by a Mitsunobu protocol adapted Gabriel synthesis. The optical purity of some of the chiral compounds was determine d (ee > 95%) by capillary electrophoresis (CE). The investigated compounds showed pronounced to high antagonist activity (K-i values of 4.1-316 nM) in a functional test for histamine H-3 receptors on rat cerebral cortex synap tosomes. Similar H-3-receptor antagonist activities were observed in a peri pheral model on guinea pig ileum. No stereoselective discrimination for the H-3 receptor for the chiral antagonists was found with the in vitro assays . All compounds were also screened for central H-3-receptor antagonist acti vity in vivo in mice after po administration. Most compounds were potent ag ents of the H-3-receptor-mediated enhancement of brain N-tau-methylhistamin e levels. The enantiomers of the N-2-heptylcarbamate showed a stereoselecti ve differentiation in their pharmacological effect in vivo (ED50 Of 0.39 mg /kg for the (S)-derivative vs 1.5 mg/kg for the (R)-derivative) most probab ly caused by differences in pharmacokinetic parameters. H-1- and H-2-ecepto r activities were determined for some of the novel carbamates, demonstratin g that they have a highly selective action at the histamine H-3 receptor.