title: New 1,2,3,9-tetrahydro-4H-carbazol-4-one derivatives: analogues of HEAT as ligands for the alpha1-adrenergic receptor subtypes.
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.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Catania, viale A. Doria 6, 95125 Catania, Italy. gromeo@mbox.unict.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Romeo
authors.forename: Luisa
authors.initials: L
authors.lastname: Materia
authors.forename: Valeria
authors.initials: V
authors.lastname: Pittalà
authors.forename: Maria
authors.initials: M
authors.lastname: Modica
authors.forename: Loredana
authors.initials: L
authors.lastname: Salerno
authors.forename: Mariangela
authors.initials: M
authors.lastname: Siracusa
authors.forename: Filippo
authors.initials: F
authors.lastname: Russo
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Minneman
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008744:Methylamines / Q000737:chemistry; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D044024:Tetralones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C513019:1,2,3,9-tetrahydro-4H-carbazol-4-one; C513020:3-(((2-(4-hydroxyphenyl)ethyl)amino)methyl); C475198:3-(2-(4-(2-(11C)methoxyphenyl)piperazin-1-yl)ethyl)pyrimido(5,4-b)indole-2,4-dione; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D002227:Carbazoles; D007211:Indoles; D008024:Ligands; D008744:Methylamines; D010879:Piperazines; D011743:Pyrimidines; D044024:Tetralones; C010652:BE 2254