New 1,2,3,9-tetrahydro-4H-carbazol-4-one derivatives: Analogues of HEAT as ligands for the α1-adrenergic receptor subtypes

With the aim to develop new ligands able to discriminate among the three subtypes of α1-adrenergic receptors (α1A-AR, α1B-AR, and α1D-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 α1-AR antagonists which show high affinities for all three α1-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 α1A-AR, α1B-AR, and α1D-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.

A series of new 1,2,3,9-tetrahydro-4H-carbazol-4-one derivatives structurally related to HEAT, a potent α1-adrenergic receptor antagonist, was synthesized. Binding affinities of new compounds for the human cloned α1-adrenergic receptor subtypes were evaluated.Figure optionsDownload as PowerPoint slide