TY  - JOUR
A1  - Vazquez-Rodriguez, Saleta
A1  - Vilar, Santiago
A1  - Kachler, Sonja
A1  - Klotz, Karl-Norbert
A1  - Uriarte, Eugenio
A1  - Borges, Fernanda
A1  - Matos, Maria João
T1  - Adenosine receptor ligands: coumarin−chalcone hybrids as modulating agents on the activity of hARs
JF  - Molecules
N2  - Adenosine receptors (ARs) play an important role in neurological and psychiatric disorders such as Alzheimer's disease, Parkinson's disease, epilepsy and schizophrenia. The different subtypes of ARs and the knowledge on their densities and status are important for understanding the mechanisms underlying the pathogenesis of diseases and for developing new therapeutics. Looking for new scaffolds for selective AR ligands, coumarin–chalcone hybrids were synthesized (compounds 1–8) and screened in radioligand binding (hA\(_1\), hA\(_{2A}\) and hA\(_3\)) and adenylyl cyclase (hA\(_{2B}\)) assays in order to evaluate their affinity for the four human AR subtypes (hARs). Coumarin–chalcone hybrid has been established as a new scaffold suitable for the development of potent and selective ligands for hA\(_1\) or hA\(_3\) subtypes. In general, hydroxy-substituted hybrids showed some affinity for the hA\(_1\), while the methoxy counterparts were selective for the hA\(_3\). The most potent hA\(_1\) ligand was compound 7 (K\(_i\) = 17.7 µM), whereas compound 4 was the most potent ligand for hA\(_3\) (K\(_i\) = 2.49 µM). In addition, docking studies with hA\(_1\) and hA\(_3\) homology models were established to analyze the structure–function relationships. Results showed that the different residues located on the protein binding pocket could play an important role in ligand selectivity.
KW  - coumarin
KW  - chalcone
KW  - neurodegenerative diseases
KW  - adenosine receptors
KW  - binding affinity
KW  - docking
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-213165
SN  - 1420-3049
VL  - 25
IS  - 18
ER  -