Abstract
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 (hA1, hA2A and hA3) and adenylyl cyclase (hA2B) 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 hA1 or hA3 subtypes. In general, hydroxy-substituted hybrids showed some affinity for the hA1, while the methoxy counterparts were selective for the hA3. The most potent hA1 ligand was compound 7 (Ki = 17.7 µM), whereas compound 4 was the most potent ligand for hA3 (Ki = 2.49 µM). In addition, docking studies with hA1 and hA3 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.
Highlights
Adenosine receptors (ARs) are cell membrane receptors, belonging to the G protein-coupled receptor (GPCRs) superfamily
We focused our attention on the 3-benzoylcoumarin core, considered as a hybrid scaffold in which the chalcone is fixed in a trans conformation through the double bond of the pyrone ring of the coumarin skeleton (Figure 1), presenting a more restricted conformation compared to the previously described coumarin–chalcone hybrids [36]
The binding affinity results show that derivatives 1 and 2, without substitutions on the coumarin scaffold or with a single methoxy group at the position 6 of the coumarin core, respectively, display no detectable binding affinity for the evaluated receptors (Ki > 100 μM)
Summary
Adenosine receptors (ARs) are cell membrane receptors, belonging to the G protein-coupled receptor (GPCRs) superfamily. ARs comprised of four different subtypes: A1 , A2A , A2B and A3 [1]. Adenosine is a purine nucleoside and an endogenous modulator of several physiological processes [1,2,3,4]. Extracellular adenosine activates the Gi -coupled receptors of the A1 and A3 subtypes, depressing the action of the brain, heart, kidneys, and the immune system, amongst other systems, as a consequence of the inhibition of adenylyl cyclase [5]. The A3 subtype of AR has been cloned [6,7], making it possible to establish its pharmacological [8,9,10,11] and regulatory features [12].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
