Abstract
In search for potent and therapeutically useful H3-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 H3-receptor antagonist activity as well as for H3-receptor selectivity versus H1- and H2-receptors. The presented 4-alkynylphenyl ethers are highly potent and selective H3 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 Ki value of 8.6 and an ED50 value of 0.12 mg/kg. At present 14a is the most potent H3-receptor antagonist in vivo and may therefore be a potential drug for the therapy of H3-receptor-dependent diseases of the central nervous system (CNS).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Cerebral Cortex / drug effects
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Cerebral Cortex / metabolism
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Cerebral Cortex / ultrastructure
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Ethers / administration & dosage
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Ethers / chemical synthesis*
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Ethers / chemistry
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Ethers / pharmacology
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Guinea Pigs
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Histamine Antagonists / administration & dosage
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Histamine Antagonists / chemical synthesis*
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Histamine Antagonists / chemistry
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Histamine Antagonists / pharmacology
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Histamine Release / drug effects
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Ileum / drug effects
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Ileum / metabolism
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Imidazoles / administration & dosage
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry
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Imidazoles / pharmacology
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In Vitro Techniques
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Mice
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Myocardium / metabolism
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Rats
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Receptors, Histamine H1 / drug effects
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Receptors, Histamine H2 / drug effects
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Receptors, Histamine H3 / drug effects*
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Synaptosomes / drug effects
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Synaptosomes / metabolism
Substances
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4-ethynylphenyl 3-(1H-imidazol-4-yl)propyl ether
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Ethers
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Histamine Antagonists
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Imidazoles
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Receptors, Histamine H1
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Receptors, Histamine H2
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Receptors, Histamine H3