4-ALKYNYLPHENYL IMIDAZOLYLPROPYL ETHERS AS SELECTIVE HISTAMINE H-3-RECEPTOR ANTAGONISTS WITH HIGH ORAL CENTRAL-NERVOUS-SYSTEM ACTIVITY

In search for potent and therapeutically useful Hs-receptor antagonist s, we prepared novel 4-alkynylphenyl ether derivatives of 3-(1H-imidaz ol-4-yl)propanol in a convenient synthetic route. All compounds were t ested for in vitro and in vivo H-3-receptor antagonist activity as wel l as for H-3-receptor selectivity versus H-1- and H-2-receptors. The p resented 4-alkynylphenyl ethers are highly potent and selective H-3 an tagonists showing oral activity and improved brain penetration. Partic ularly 4-ethynylphenyl 3-(1H-imidazol-4-yl)propyl ether (14a) displays striking in vitro and in vivo activity with a -log K-i value of 8.6 a ha an ED50 value of 0.12 mg/kg. At present 14a is the most potent H-3- receptor antagonist in vivo and may therefore be a potential drug for the therapy of H-3-receptor-dependent diseases of the central nervous system (CNS).