New Pyrimido[5,4-b]indoles as Ligands for α<INF>1</INF>-Adrenoceptor Subtypes

A new series of compounds were designed as structural analogues of the α<INF>1</INF>-AR ligand RN5 (<BO>4</BO>), 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<INF>1A</INF>-AR, α<INF>1B</INF>-AR, and α<INF>1D</INF>-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<INF>1D</INF>-AR subtype. Some compounds, including <BO>39</BO> and <BO>40</BO>, displayed substantial α<INF>1D</INF>-AR selectivity with respect to α<INF>1A</INF>-AR, α<INF>1B</INF>-AR, serotonergic 5-HT<INF>1A</INF>, 5-HT<INF>1B</INF>, 5-HT<INF>2A</INF>, and dopaminergic D<INF>1</INF> and D<INF>2</INF> receptors. Two conformationally rigid analogues of <BO>4</BO>, 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<INF>1D</INF>-AR antagonists, based on a more generalized model we had developed for α<INF>1</INF>-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.