New Pyrimido[5,4-b]indoles as Ligands for α1-Adrenoceptor Subtypes

A new series of compounds were designed as structural analogues of the α1-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 α1A-AR, α1B-AR, and α1D-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 α1D-AR subtype. Some compounds, including 39 and 40, displayed substantial α1D-AR selectivity with respect to α1A-AR, α1B-AR, serotonergic 5-HT1A, 5-HT1B, 5-HT2A, and dopaminergic D1 and D2 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 α1D-AR antagonists, based on a more generalized model we had developed for α1-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.