New Pyrimido[5,4-b]indoles as Ligands for α_1-Adrenoceptor Subtypes

摘要

A new series of compounds were designed as structural analogues of the α_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 α_(1A)-AR, α_(1B)-AR, and α_(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 α_(1D)-AR subtype. Some compounds, including 39 and 40, displayed substantial α_(1D)-AR selectivity with respect to α_(1A)-AR, α_(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 α_(1D)-AR antagonists, based on a more generalized model we had developed for α_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.