Romeo Giuseppe, Materia Luisa, Manetti Fabrizio, Cagnotto Alfredo, Mennini Tiziana, Nicoletti Ferdinando, Botta Maurizio, Russo Filippo, Minneman Kenneth P
Dipartimento di Scienze Farmaceutiche, Università di Catania, Viale A Doria 6, 95125 Catania, Italy.
J Med Chem. 2003 Jul 3;46(14):2877-94. doi: 10.1021/jm0307741.
A new series of compounds were designed as structural analogues of the alpha(1)-AR ligand RN5 (4), characterized by a tricyclic 5H-pyrimido[5,4-b]indole-(1H,3H)2,4-dione system connected through an alkyl chain to a phenylpiperazine (PP) moiety. These compounds were synthesized and tested in binding assays on human alpha(1A)-AR, alpha(1B)-AR, and alpha(1D)-AR subtypes expressed in HEK293 cells. Several structural modifications were performed on the PP moiety, the tricyclic system, and the connecting alkyl chain. Many of the new molecules showed a preferential affinity for the alpha(1D)-AR subtype. Some compounds, including 39 and 40, displayed substantial alpha(1D)-AR selectivity with respect to alpha(1A)-AR, alpha(1B)-AR, serotonergic 5-HT(1A), 5-HT(1B), 5-HT(2A), and dopaminergic D(1) and D(2) receptors. Two conformationally rigid analogues of 4, useful for studying the architecture of the receptor/ligand complex, were also prepared and tested. A subset of the new compounds was then used to evolve a preliminary pharmacophore model for alpha(1D)-AR antagonists, based on a more generalized model we had developed for alpha(1)-AR antagonists. This new model rationalized the relationships between structural properties and biological data of the pyrimido[5,4-b]indole compounds, as well as other compounds.
设计了一系列新化合物作为α(1)-AR配体RN5 (4)的结构类似物，其特征是通过烷基链连接到苯基哌嗪(PP)部分的三环5H-嘧啶并[5,4-b]吲哚-(1H,3H)2,4-二酮体系。合成了这些化合物，并在HEK293细胞中表达的人α(1A)-AR、α(1B)-AR和α(1D)-AR亚型的结合试验中进行了测试。对PP部分、三环体系和连接烷基链进行了几种结构修饰。许多新分子对α(1D)-AR亚型表现出优先亲和力。一些化合物，包括39和40，相对于α(1A)-AR、α(1B)-AR、血清素能5-HT(1A)、5-HT(1B)、5-HT(2A)以及多巴胺能D(1)和D(2)受体，表现出显著的α(1D)-AR选择性。还制备并测试了4的两种构象刚性类似物，它们可用于研究受体/配体复合物的结构。然后，基于我们为α(1)-AR拮抗剂开发的更通用模型，使用一部分新化合物来推导α(1D)-AR拮抗剂的初步药效团模型。这个新模型合理化了嘧啶并[5,4-b]吲哚化合物以及其他化合物的结构性质与生物学数据之间的关系。
