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

Subtype-selective Noncompetitive or Competitive Inhibition of Human α1-Adrenergic Receptors by ρ-TIA

“…Cell Culture and Transfection-HEK293 cells stably expressing human ␣ 1A -(31), ␣ 1B -(7), or ␣ 1D -(9)ARs have been previously described (32). Cells were propagated in Dulbecco's modified Eagle's medium containing 10% calf serum, 4.5g/liter glucose, 100 mg/liter streptomycin, and 10 5 units/liter penicillin at 37°C in a humidified atmosphere with 5% CO 2 .…”

Crystal structure of 1-((2R,3S)-2,3-dimethyl-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenoxyethan-1-one, C18H19NO3

“…Moreover, they also act as useful intermeditates in the syntheses of compounds with therapeutic interest [4,5]. In continuation of our interest in the development of N-containing heterocyclic compounds, herein we report a 1,4-benzoxazine [6,7].…”

3D-QSAR CoMFA and CoMSIA studies on a set of diverse α1a-adrenergic receptor antagonists

“…A general a 1 -ARs pharmacophore developed by Barbaro et al (2001) was based on pyridazinone derivatives (Fang et al, 2003) while Li et al (2005) developed an a 1a pharmacophore based on a diverse class of compounds. Recently, selective pharmacophore for a 1 -ARs subtype was developed by MacDougall and Griffith (2006) while a 1d -ARs subtype specific pharmacophore was developed by Romeo et al (2003). A CoMFA study on hexahydro and octahydropyrido[1,2-c]pyrimidine derivatives as a 1a -AR antagonists has been reported (Maciejewska et al, 2006) while a self-organizing molecular field analysis (SOMFA) method to provide insight for the development of a 1 -adrenoceptor antagonists has been carried out by Li and Xia (2007)).…”