A2A Adenosine Receptor Antagonists: Are Triazolotriazine and Purine Scaffolds Interchangeable?

Abstract

The A2A adenosine receptor (A2AAR) is one of the four subtypes activated by nucleoside adenosine, and the molecules able to selectively counteract its action are attractive tools for neurodegenerative disorders. In order to find novel A2AAR ligands, two series of compounds based on purine and triazolotriazine scaffolds were synthesized and tested at ARs. Compound 13 was also tested in an in vitro model of neuroinflammation. Some compounds were found to possess high affinity for A2AAR, and it was observed that compound 13 exerted anti-inflammatory properties in microglial cells. Molecular modeling studies results were in good agreement with the binding affinity data and underlined that triazolotriazine and purine scaffolds are interchangeable only when 5- and 2-positions of the triazolotriazine moiety (corresponding to the purine 2- and 8-positions) are substituted.

“Dual Anta-Inhibitors” of the A2A Adenosine Receptor and Casein Kinase CK1delta: Synthesis, Biological Evaluation, and Molecular Modeling Studies

“…All of the pharmacological methods followed the procedures as described earlier [ 25 ]. In brief, the membranes for radioligand binding were prepared from CHO cells stably transfected with human adenosine receptor subtypes through two centrifugations at different speeds.…”

“…The binding affinity of the novel compounds was evaluated using radioligand competition experiments in CHO cells stably expressing hA 1 AR, hA 2A AR, hA 3 AR subtypes, as early described [ 25 ]. Results were expressed as K i values (dissociation constants), which were calculated with the program GraphPad (GraphPad Software, San Diego, CA, USA).…”

“…With this concept in mind, and in the search for new CK1δ inhibitors, we selected and tested a series of adenine derivatives available in our chemical library and previously designed and synthesized as A 2A AR antagonists [ 24 , 25 , 26 ]. These compounds were tested on truncated CK1δ enzyme, which lacks the autoregulatory inhibitory portion present in the C-terminal domain.…”

Sequential, Electrochemical‐Photochemical Synthesis of 1,2,4‐Triazolo‐[4,3‐a]pyrazines

“…A 2a AR is one of the 4 types of adenosine receptors (A 1 , A 2a , A 2b , A 3 ) and has garnered attention for drug design. Both A 2a AR and A 2b AR are coupled to G stimulatory proteins, which produce the secondary messenger cyclic adenosine monophosphate (cAMP) when activated [17] . cAMP, a purine nucleotide, regulates both pro‐ and anti‐inflammatory responses within the immune system [18] .…”

Microwave-Assisted Synthesis, Structure, and Preliminary Biological Evaluation of Novel 6-Methoxy-5,6-dihydro-5-azapurines

“…5-Azapurines or 1,2,4-triazolo­[1,5- a ]­[1,3,5]­triazines are considered purine isosteres possessing an additional nitrogen atom in the fifth position of their bicyclic cores. The structural similarity of 5-azapurines to purines makes this scaffold promising for drug development, since the purine core is often found in developmental and clinically used drugs, such as acyclovir, mercaptopurine, diphylline, etc. − In particular, 5-azapurines are of great interest for the development of new thymidine phosphorylase inhibitors, selective adenosine receptor ligands, − and antiproliferative agents (e.g., compounds 1 – 3 , Figure ). Apart from being useful in medicinal chemistry, 5-azapurines are also known as potential thermostable high-energy sources − as well as highly efficient thermally activated delayed fluorescence materials that are highly promising in the construction of new types of OLED-based displays. , Structurally related to 5-azapurines, substituted purines and purine-like compounds exhibiting 6-alkylamino or 6-alkoxy groups have also been described in the literature.…”