21316
2020
eng
18
25
article
1
--
2020-09-19
--
Adenosine receptor ligands: coumarin−chalcone hybrids as modulating agents on the activity of hARs
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.
Molecules
1420-3049
10.3390/molecules25184306
urn:nbn:de:bvb:20-opus-213165
swordwue
2020-10-08T03:04:10+00:00
attachment; filename=deposit.zip
28c6ebb1831f3eb720a9abe5d88d986e
Molecules (2020) 25:18, 4306. https://doi.org/10.3390/molecules25184306
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Saleta Vazquez-Rodriguez
Santiago Vilar
Sonja Kachler
Karl-Norbert Klotz
Eugenio Uriarte
Fernanda Borges
Maria João Matos
eng
uncontrolled
coumarin
eng
uncontrolled
chalcone
eng
uncontrolled
neurodegenerative diseases
eng
uncontrolled
adenosine receptors
eng
uncontrolled
binding affinity
eng
uncontrolled
docking
Chemie und zugeordnete Wissenschaften
Pharmakologie, Therapeutik
open_access
Institut für Pharmakologie und Toxikologie
Import
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/21316/molecules-25-04306-v2.pdf
13713
2015
eng
e0143504
12
10
article
1
2016-08-09
--
--
The Influence of the 1-(3-Trifluoromethyl-Benzyl)-1H-Pyrazole-4-yl Moiety on the Adenosine Receptors Affinity Profile of Pyrazolo[4,3-e][1,2,4]Triazolo[1,5-c]Pyrimidine Derivatives
A new series of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (PTP) derivatives has been developed in order to explore their affinity and selectivity profile at the four adenosine receptor subtypes. In particular, the PTP scaffold was conjugated at the C2 position with the 1-(3-trifluoromethyl-benzyl)-1H-pyrazole, a group believed to confer potency and selectivity toward the human (h) A\(_{2B}\) adenosine receptor (AR) to the xanthine ligand 8-(1-(3-(trifluoromethyl) benzyl)-1H-pyrazol-4-yl)-1,3-dimethyl-1H-purine-2,6(3H, 7H)-dione (CVT 6975). Interestingly, the synthesized compounds turned out to be inactive at the hA\(_{2B}\) AR but they displayed affinity at the hA\(_3\) AR in the nanomolar range. The best compound of the series (6) shows both high affinity (hA\(_3\) AR K\(_i\) = 11 nM) and selectivity (A\(_1\)/A\(_3\) and A\(_{2A}\)/A\(_3\) > 9090; A\(_{2B}\)/A\(_3\) > 909) at the hA\(_3\) AR. To better rationalize these results, a molecular docking study on the four AR subtypes was performed for all the synthesized compounds. In addition, CTV 6975 and two close analogues have been subjected to the same molecular docking protocol to investigate the role of the 1-(3-trifluoromethyl-benzyl)-1H-pyrazole on the binding at the four ARs.
PLoS One
10.1371/journal.pone.0143504
urn:nbn:de:bvb:20-opus-137133
PLoS ONE 10(12): e0143504. doi:10.1371/journal.pone.0143504
Stephanie Federico
Sara Redenti
Mattia Sturlese
Antonella Ciancetta
Sonja Kachler
Karl-Norbert Klotz
Barbara Cacciari
Stefano Moro
Giampiero Spalluto
eng
uncontrolled
drug
eng
uncontrolled
human A(3)
eng
uncontrolled
protein-coupled receptors
eng
uncontrolled
classification
eng
uncontrolled
subtypes
eng
uncontrolled
potent
eng
uncontrolled
antagonists
eng
uncontrolled
mast cells
eng
uncontrolled
targets
eng
uncontrolled
A(2B) receptors
eng
uncontrolled
international union
Medizin und Gesundheit
open_access
Institut für Pharmakologie und Toxikologie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/13713/Federico.pdf