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

• Published in: Journal of medicinal chemistry Vol. 46; no. 14; pp. 2877 - 2894
• Main Authors: Romeo, Giuseppe, Materia, Luisa, Manetti, Fabrizio, Cagnotto, Alfredo, Mennini, Tiziana, Nicoletti, Ferdinando, Botta, Maurizio, Russo, Filippo, Minneman, Kenneth P
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 03.07.2003
• Subjects: Biological and medical sciences; Catecholaminergic system; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Nitrogen heterocycle; Prediction; α1-Adrenergic receptor; Selectivity; Tricyclic compound; In vitro; Modeling; Biological fixation; Cell line; Structure activity relation; Molecular model; Aromatic compound; Piperazine derivatives; α1D-adrenergic receptor; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0307741

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.