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 alpha(1)-adrenergic receptors (alpha(1A)-AR, alpha(1B)-AR, and alpha(1D)-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 alpha(1)-AR antagonists which show high affinities for all three alpha(1)-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 alpha(1A)-AR, alpha(1B)-AR, and alpha(1D)-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. (c) 2006 Elsevier Ltd. All rights reserved.