Substituted N-phenylcarbamates as histamine H3 receptor antagonists with improved in vivo potency

Novel substituted N-phenylcarbamates as derivatives of 3-(1 H-imidazol-4-yl)propanol were prepared and tested for their antagonist potency in vitro and in vivo at histamine H3 receptors. Structural modifications with different alkyl and acetyl moieties were performed in an attempt to optimize pharmacodynamic and pharmacokinetic effects. Most compounds are active in a functional test for histamine H3 receptors on rat cerebral cortex synaptosomes as well as in a peripheral model on guinea pig ileum. But only carbamates without too bulky lipophilic residues showed pronounced to high antagonist potency on the enhancement of endogenous histamine in brain after p.o. administration to mice (ED50 values of 5.5 to 0.86 mg.kg-1). The tested compounds presented weak activities at histamine H1, H2, and muscarinic M3 receptors thus demonstrating their H3-receptor selectivity.