Abstract
Three series of H(4) receptor ligands, derived from indoly-2-yl-(4-methyl-piperazin-1-yl)-methanones, have been synthesized and their structure-activity relationships evaluated for activity at the H(4) receptor in competitive binding and functional assays. In all cases, substitution of small lipophilic groups in the 4 and 5-positions led to increased activity in a [(3)H]histamine radiolabeled ligand competitive binding assay. In vitro metabolism and initial pharmacokinetic studies were performed on selected compounds leading to the identification of indole 8 and benzimidazole 40 as potent H(4) antagonists with the potential for further development. In addition, both 8 and 40 demonstrated efficacy in in vitro mast cell and eosinophil chemotaxis assays.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzimidazoles / chemical synthesis
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Benzimidazoles / pharmacokinetics
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Benzimidazoles / pharmacology
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Binding, Competitive
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Cell Line, Tumor
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Chemotaxis, Leukocyte / drug effects
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Eosinophils / drug effects
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Histamine Antagonists / chemical synthesis*
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Histamine Antagonists / pharmacokinetics
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Histamine Antagonists / pharmacology*
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Humans
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Indoles / chemical synthesis
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Indoles / pharmacokinetics
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Indoles / pharmacology
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Mast Cells / drug effects
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Mice
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Piperazines / chemical synthesis*
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Piperazines / pharmacokinetics
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Piperazines / pharmacology*
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Rats
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Receptors, G-Protein-Coupled / antagonists & inhibitors*
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Receptors, Histamine
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Receptors, Histamine H4
Substances
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Benzimidazoles
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HRH4 protein, human
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Histamine Antagonists
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Indoles
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Piperazines
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Receptors, G-Protein-Coupled
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Receptors, Histamine
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Receptors, Histamine H4