Multicomponent Synthesis and Biological Evaluation of a Piperazine-Based Dopamine Receptor Ligand Library

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• 作者：Mattia Stucchi ; Peter Gmeiner ; Harald Huebner ; Giulia Rainoldi ; Alessandro Sacchetti ; Alessandra Silvani ; Giordano Lesma
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：August 13, 2015
• 年：2015
• 卷：6
• 期：8
• 页码：882-887
• 全文大小：408K
• ISSN：1948-5875

文摘

A series of 1,4-disubstituted piperazine-based compounds were designed, synthesized, and evaluated as dopamine D2/D3 receptor ligands. The synthesis relies on the key multicomponent split-Ugi reaction, assessing its great potential in generating chemical diversity around the piperazine core. With the aim of evaluating the effect of such diversity on the dopamine receptor affinity, a small library of compounds was prepared, applying post-Ugi transformations. Ligand stimulated binding assays indicated that some compounds show a significant affinity, with K_i values up to 53 nM for the D2 receptor. Molecular docking studies with the D2 and D3 receptor homology models were also performed on selected compounds. They highlighted key interactions at the indole head and at the piperazine moiety, which resulted in good agreement with the known pharmacophore models, thus helping to explain the observed structure鈥揳ctivity relationship data. Molecular insights from this study could enable a rational improvement of the split-Ugi primary scaffold, toward more selective ligands.