Abstract
With the aim to develop new ligands able to discriminate among the three subtypes of alpha1-adrenergic receptors (alpha1A-AR, alpha1B-AR, and alpha1D-AR), a series of new 1,2,3,9-tetrahydro-4H-carbazol-4-ones bearing a 3-[[[2-(4-hydroxyphenyl)ethyl]amino]methyl] or a 3-[[4-(2-substitutedphenyl)piperazin-1-yl]methyl] side chain were synthesized. The general structure of the new compounds is reminiscent of HEAT and RN5, two potent alpha1-AR antagonists which show high affinities for all three alpha1-AR subtypes. Some derivatives in which one ring of the tetrahydrocarbazolone system was opened were also prepared. Compounds were tested in radioligand binding assays on human cloned alpha1A-AR, alpha1B-AR, and alpha1D-AR subtypes stably expressed in HEK293 cells. They showed moderate to good affinities, although their selectivity among the receptor subtypes hardly reached one order of magnitude.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenergic alpha-1 Receptor Antagonists*
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Adrenergic alpha-Antagonists / chemical synthesis
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Adrenergic alpha-Antagonists / chemistry
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Adrenergic alpha-Antagonists / pharmacology*
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Binding Sites
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Carbazoles / chemical synthesis
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Carbazoles / chemistry
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Carbazoles / pharmacology*
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Cell Line
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Cells, Cultured
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Humans
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Indoles / chemical synthesis
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Indoles / chemistry
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Indoles / pharmacology*
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Ligands
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Methylamines / chemistry
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Molecular Structure
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Piperazines / chemistry
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Structure-Activity Relationship
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Tetralones / chemical synthesis
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Tetralones / chemistry
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Tetralones / pharmacology*
Substances
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1,2,3,9-tetrahydro-4H-carbazol-4-one
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3-(((2-(4-hydroxyphenyl)ethyl)amino)methyl)
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3-(2-(4-(2-(11C)methoxyphenyl)piperazin-1-yl)ethyl)pyrimido(5,4-b)indole-2,4-dione
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Adrenergic alpha-1 Receptor Antagonists
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Adrenergic alpha-Antagonists
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Carbazoles
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Indoles
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Ligands
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Methylamines
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Piperazines
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Pyrimidines
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Tetralones
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BE 2254