DEVELOPMENT OF FUB-181, A SELECTIVE HISTAMINE H-3-RECEPTOR ANTAGONISTOF HIGH ORAL IN-VIVO POTENCY WITH 4-(OMEGA-(ARYLALKYLOXY)ALKYL)-1H-IMIDAZOLE STRUCTURE

A series of 4-(omega-(arylalkyloxy)alkyl)-1H-imidazoles and related su lphur-containing compounds have been prepared and evaluated for their histamine H-3-autoreceptor antagonist in vitro potency in an assay on synaptosomes of rat cerebral cortex. In addition, the in vivo potency has been determined from the changes in N-tau-methylhistamine levels i n brain after p.o. administration to mice. Compounds with different al kyl chains and various aryl moities have been synthesized and tested t o explore structure-activity relationships. Within this series of nove l antagonists, (1H-imidazol-4-yl)methyl and 2-(1H-imidazol-4-yl)ethyl ether derivatives showed low to moderate H-3-receptor antagonist poten cy, whereas the corresponding allyl and propyl derivatives were compou nds with high antagonist irt vitro potency. Corresponding thioether or sulphoxide derivatives also showed antagonist activity. Additionally, some ether derivatives possessed high in vivo potency as well. The mo st active ether derivatives under in vivo conditions were 4-(3-(3-(4-f luorophenyl)propyloxy)propyl) 1H-imidazole (11b) and the corresponding chloro compound 11c (FUB 181) with ED50 values of 0.76 and 0.80 mg/kg , respectively. On the other hand, all compounds tested showed weak ac tivity at histamine H-1 or H-2 receptors, Furthermore, the most promis ing ether FUB 181 exhibited low activity at adrenergic alpha(1), beta( 1/2), serotonergic 5-HT2A, 5-HT3, and muscarinic M-3 receptors. Time-c ourse investigations of FUB 181 in mice showed a rapid mode of action with the highest value 3 h after p.o. application. Thus, FUB 181 appea rs to block histamine H-3 receptors potently and selectively.