304905-24-6Relevant articles and documents
Piperazine-and piperidine-containing thiazolo[5,4-d]pyrimidine derivatives as new potent and selective adenosine a2a receptor inverse agonists
Varano, Flavia,Catarzi, Daniela,Vigiani, Erica,Vincenzi, Fabrizio,Pasquini, Silvia,Varani, Katia,Colotta, Vittoria
, p. 1 - 19 (2020/07/31)
The therapeutic use of A2A adenosine receptor (AR) antagonists for the treatment of neurodegenerative disorders, such as Parkinson and Alzheimer diseases, is a very promising approach. Moreover, the potential therapeutic role of A2A AR antagonists to avoid both immunoescaping of tumor cells and tumor development is well documented. Herein, we report on the synthesis and biological evaluation of a new set of piperazine-and piperidine-containing 7-amino-2-(furan-2-yl)thiazolo[5,4-d]pyrimidine derivatives designed as human A2A AR antagonists/inverse agonists. Binding and potency data indicated that a good number of potent and selective hA2A AR inverse agonists were found. Amongst them, the 2-(furan-2-yl)-N5-(2-(4-phenylpiperazin-1-yl)ethyl)thiazolo[5,4-d]pyrimidine-5,7-diamine 11 exhibited the highest A2A AR binding affinity (Ki = 8.62 nM) as well as inverse agonist potency (IC50 = 7.42 nM). In addition, bioinformatics prediction using the web tool SwissADME revealed that 8, 11, and 19 possessed good drug-likeness profiles.
Another brick in the wall. Validation of the σ1 receptor 3d model by computer-assisted design, synthesis, and activity of new σ1 ligands
Laurini, Erik,Marson, Domenico,Dal Col, Valentina,Fermeglia, Maurizio,Mamolo, Maria Grazia,Zampieri, Daniele,Vio, Luciano,Pricl, Sabrina
, p. 3107 - 3126 (2013/01/15)
Originally considered an enigmatic polypeptide, the σ1 receptor has recently been identified as a unique ligand-regulated protein. Many studies have shown the potential of σ1 receptor ligands for the treatment of various diseases of the central nervous system (CNS); nevertheless, almost no information about the 3D structure of the receptor and/or the possible modes of interaction of the σ1 protein with its ligands have been unveiled so far. With the present work we validated our σ1 3D homology model and assessed its reliability as a platform for σ1 ligand structure-based drug design. To this purpose, the 3D σ1 model was exploited in the design of 33 new σ1 ligands and in their ranking for receptor affinity by extensive molecular dynamics simulation-based free energy calculations. Also, the main interactions involved in receptor/ligand binding were analyzed by applying a per residue free energy deconvolution and in silico alanine scanning mutagenesis calculations. Subsequently, all compounds were synthesized in our laboratory and tested for σ1 binding activity in vitro. The agreement between in silico and in vitro results confirms the reliability of the proposed σ1 3D model in the a priori prediction of the affinity of new σ1 ligands. Moreover, it also supports and corroborates the currently available biochemical data concerning the σ1 protein residues considered essential for σ1 ligand binding and activity.
