Adenosine Receptor Ligands: Coumarin–Chalcone Hybrids as Modulating Agents on the Activity of <i>h</i>ARs
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 underl...
Main Authors: | , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2020-09-01
|
Series: | Molecules |
Subjects: | |
Online Access: | https://www.mdpi.com/1420-3049/25/18/4306 |
id |
doaj-c37473a590204b378004fac5703d705d |
---|---|
record_format |
Article |
spelling |
doaj-c37473a590204b378004fac5703d705d2020-11-25T03:43:30ZengMDPI AGMolecules1420-30492020-09-01254306430610.3390/molecules25184306Adenosine Receptor Ligands: Coumarin–Chalcone Hybrids as Modulating Agents on the Activity of <i>h</i>ARsSaleta Vazquez-Rodriguez0Santiago Vilar1Sonja Kachler2Karl-Norbert Klotz3Eugenio Uriarte4Fernanda Borges5Maria João Matos6Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, SpainDepartamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, SpainInstitut für Pharmakologie und Toxikologie, Universität Würzburg, 97078, Würzburg, GermanyInstitut für Pharmakologie und Toxikologie, Universität Würzburg, 97078, Würzburg, GermanyDepartamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, SpainCIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua Campo Alegre 687, 4169-007 Porto, PortugalDepartamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, SpainAdenosine 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 <strong>1</strong>–<strong>8</strong>) and screened in radioligand binding (<em>h</em>A<sub>1</sub>, <em>h</em>A<sub>2A</sub> and <em>h</em>A<sub>3</sub>) and adenylyl cyclase (<em>h</em>A<sub>2B</sub>) assays in order to evaluate their affinity for the four human AR subtypes (<em>h</em>ARs). Coumarin–chalcone hybrid has been established as a new scaffold suitable for the development of potent and selective ligands for <em>h</em>A<sub>1</sub> or <em>h</em>A<sub>3</sub> subtypes. In general, hydroxy-substituted hybrids showed some affinity for the <em>h</em>A<sub>1</sub>, while the methoxy counterparts were selective for the <em>h</em>A<sub>3</sub>. The most potent <em>h</em>A<sub>1</sub> ligand was compound <strong>7 </strong>(<em>K</em><sub>i</sub> = 17.7 µM), whereas compound <strong>4</strong> was the most potent ligand for <em>h</em>A<sub>3</sub> (<em>K</em><sub>i</sub> = 2.49 µM). In addition, docking studies with <em>h</em>A<sub>1</sub> and <em>h</em>A<sub>3</sub> 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.https://www.mdpi.com/1420-3049/25/18/4306n/a |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Saleta Vazquez-Rodriguez Santiago Vilar Sonja Kachler Karl-Norbert Klotz Eugenio Uriarte Fernanda Borges Maria João Matos |
spellingShingle |
Saleta Vazquez-Rodriguez Santiago Vilar Sonja Kachler Karl-Norbert Klotz Eugenio Uriarte Fernanda Borges Maria João Matos Adenosine Receptor Ligands: Coumarin–Chalcone Hybrids as Modulating Agents on the Activity of <i>h</i>ARs Molecules n/a |
author_facet |
Saleta Vazquez-Rodriguez Santiago Vilar Sonja Kachler Karl-Norbert Klotz Eugenio Uriarte Fernanda Borges Maria João Matos |
author_sort |
Saleta Vazquez-Rodriguez |
title |
Adenosine Receptor Ligands: Coumarin–Chalcone Hybrids as Modulating Agents on the Activity of <i>h</i>ARs |
title_short |
Adenosine Receptor Ligands: Coumarin–Chalcone Hybrids as Modulating Agents on the Activity of <i>h</i>ARs |
title_full |
Adenosine Receptor Ligands: Coumarin–Chalcone Hybrids as Modulating Agents on the Activity of <i>h</i>ARs |
title_fullStr |
Adenosine Receptor Ligands: Coumarin–Chalcone Hybrids as Modulating Agents on the Activity of <i>h</i>ARs |
title_full_unstemmed |
Adenosine Receptor Ligands: Coumarin–Chalcone Hybrids as Modulating Agents on the Activity of <i>h</i>ARs |
title_sort |
adenosine receptor ligands: coumarin–chalcone hybrids as modulating agents on the activity of <i>h</i>ars |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2020-09-01 |
description |
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 <strong>1</strong>–<strong>8</strong>) and screened in radioligand binding (<em>h</em>A<sub>1</sub>, <em>h</em>A<sub>2A</sub> and <em>h</em>A<sub>3</sub>) and adenylyl cyclase (<em>h</em>A<sub>2B</sub>) assays in order to evaluate their affinity for the four human AR subtypes (<em>h</em>ARs). Coumarin–chalcone hybrid has been established as a new scaffold suitable for the development of potent and selective ligands for <em>h</em>A<sub>1</sub> or <em>h</em>A<sub>3</sub> subtypes. In general, hydroxy-substituted hybrids showed some affinity for the <em>h</em>A<sub>1</sub>, while the methoxy counterparts were selective for the <em>h</em>A<sub>3</sub>. The most potent <em>h</em>A<sub>1</sub> ligand was compound <strong>7 </strong>(<em>K</em><sub>i</sub> = 17.7 µM), whereas compound <strong>4</strong> was the most potent ligand for <em>h</em>A<sub>3</sub> (<em>K</em><sub>i</sub> = 2.49 µM). In addition, docking studies with <em>h</em>A<sub>1</sub> and <em>h</em>A<sub>3</sub> 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. |
topic |
n/a |
url |
https://www.mdpi.com/1420-3049/25/18/4306 |
work_keys_str_mv |
AT saletavazquezrodriguez adenosinereceptorligandscoumarinchalconehybridsasmodulatingagentsontheactivityofihiars AT santiagovilar adenosinereceptorligandscoumarinchalconehybridsasmodulatingagentsontheactivityofihiars AT sonjakachler adenosinereceptorligandscoumarinchalconehybridsasmodulatingagentsontheactivityofihiars AT karlnorbertklotz adenosinereceptorligandscoumarinchalconehybridsasmodulatingagentsontheactivityofihiars AT eugeniouriarte adenosinereceptorligandscoumarinchalconehybridsasmodulatingagentsontheactivityofihiars AT fernandaborges adenosinereceptorligandscoumarinchalconehybridsasmodulatingagentsontheactivityofihiars AT mariajoaomatos adenosinereceptorligandscoumarinchalconehybridsasmodulatingagentsontheactivityofihiars |
_version_ |
1724519447667933184 |