title: New pyrimido[5,4-b]indoles as ligands for alpha(1)-adrenoceptor subtypes.
abstract: 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.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Catania, Viale A Doria 6, 95125 Catania, Italy. gromeo@mbox.unict.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Romeo
authors.forename: Luisa
authors.initials: L
authors.lastname: Materia
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cagnotto
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mennini
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.forename: Filippo
authors.initials: F
authors.lastname: Russo
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Minneman
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D003198:Computer Simulation; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: C547719:ADRA1D protein, human; D000317:Adrenergic alpha-Antagonists; D007211:Indoles; D008024:Ligands; D011743:Pyrimidines; D018340:Receptors, Adrenergic, alpha-1