Romeo Giuseppe, Materia Luisa, Pittalà Valeria, Modica Maria, Salerno Loredana, Siracusa Mariangela, Russo Filippo, Minneman Kenneth P
Dipartimento di Scienze Farmaceutiche, Università di Catania, viale A. Doria 6, 95125 Catania, Italy.
Bioorg Med Chem. 2006 Aug 1;14(15):5211-9. doi: 10.1016/j.bmc.2006.04.002. Epub 2006 May 2.
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.
为了开发能够区分α1 - 肾上腺素能受体三种亚型（α1A - AR、α1B - AR和α1D - AR）的新型配体，合成了一系列带有3 - [[[2 - (4 - 羟基苯基)乙基]氨基]甲基]或3 - [[4 - (2 - 取代苯基)哌嗪 - 1 - 基]甲基]侧链的新型1,2,3,9 - 四氢 - 4H - 咔唑 - 4 - 酮。新化合物的一般结构让人联想到HEAT和RN5这两种有效的α1 - AR拮抗剂，它们对所有三种α1 - AR亚型都表现出高亲和力。还制备了一些其中四氢咔唑酮系统的一个环被打开的衍生物。在稳定表达于HEK293细胞中的人克隆α1A - AR、α1B - AR和α1D - AR亚型上，用放射性配体结合试验对化合物进行了测试。它们表现出中等至良好的亲和力，尽管它们在受体亚型之间的选择性几乎未达到一个数量级。
