4-Alkynylphenyl imidazolylpropyl ethers as selective histamine H3-receptor antagonists with high oral central nervous system activity.

In search for potent and therapeutically useful Hs-receptor antagonists, we prepared novel 4-alkynylphenyl ether derivatives of 3-(1H-imidazol-4-yl)propanol in a convenient synthetic route. All compounds were tested for in vitro and in vivo H-3-receptor antagonist activity as well as for H-3-receptor selectivity versus H-1- and H-2-receptors. The presented 4-alkynylphenyl ethers are highly potent and selective H-3 antagonists showing oral activity and improved brain penetration. Particularly 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 aha 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).