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<inf>i</inf> 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-activity relationship data. Molecular insights from this study could enable a rational improvement of the split-Ugi primary scaffold, toward more selective ligands.
Multicomponent Synthesis and Biological Evaluation of a Piperazine-Based Dopamine Receptor Ligand Library / M. Stucchi, P. Gmeiner, H. Huebner, G. Rainoldi, A. Sacchetti, A. Silvani, G. Lesma. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - 6:8(2015 Jun 23), pp. 882-887.
|Titolo:||Multicomponent Synthesis and Biological Evaluation of a Piperazine-Based Dopamine Receptor Ligand Library|
|Parole Chiave:||D2/D3 dopamine receptor; molecular docking; Multicomponent reaction; split-Ugi; Organic Chemistry; Drug Discovery Pharmaceutical Science; Biochemistry|
|Settore Scientifico Disciplinare:||Settore CHIM/06 - Chimica Organica|
|Data di pubblicazione:||23-giu-2015|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1021/acsmedchemlett.5b00131|
|Appare nelle tipologie:||01 - Articolo su periodico|