Previous studies explored 2-benzylidine-1-tetralone derivatives as innovative adenosine A1 and A2A receptor antagonists for alternative non-dopaminergic treatment of Parkinson’s disease. This study’s aim is to investigate structurally related 2-benzylidene-1-indanones with substitutions on ring A and B as novel, potent and selective adenosine A1 and A2A receptor blockers. 2-Benzylidene-1-indanone derivatives were synthesised via acid catalysed aldol condensation reactions and evaluated via radioligand binding assays to ascertain structure activity relationships to govern A1 and A2A AR affinity. The results indicated that hydroxy substitution at C4 of ring A and meta (3’), or para (4’) substitution on ring B of the 2-benzylidene-1-indanone scaffold (2c) is preferred over substitution at C5 (2d) or C6 (2e) of ring A for adenosine A1 receptor activity and selectivity in the micromolar range. Furthermore, substitution at the meta (3’) position of ring B with chlorine lead to the highly potent and selective adenosine A2A receptor antagonist, compound 2 h. Compound 2c and the 2q behaved as adenosine A1 receptor antagonists in the performed GTP shift assays. In view of these findings, compounds 2c, 2 h, 2q and 2p are potent and selective adenosine A1 and A2A receptor antagonists for the potential treatment of neurological conditions.
Antagonists of the adenosine receptors (A1 and A2A) are thought to be beneficial in neurological disorders, such as Alzheimer's and Parkinson's disease. The aim of this study was to explore 2‐benzylidene‐1‐tetralone derivatives as antagonists of A1 and/or A2A adenosine receptors. In general, the test compounds were found to be selective for the A1 adenosine receptor, with only three test compounds possessing affinity for both the A1 and A2A adenosine receptor. The 2‐benzylidene‐1‐tetralones bearing a hydroxyl substituent at either position C5, C6 or C7 of ring A displayed favourable adenosine A1 receptor binding, while C5 hydroxy substitution led to favourable A2A adenosine receptor affinity. Interestingly, para‐hydroxy substitution on ring B in combination with ring A bearing a hydroxy at position C6 or C7 provided the 2‐benzylidene‐1‐tetralones with both A1 and A2A adenosine receptor affinity. Compounds 4 and 8 displayed the highest A1 and A2A adenosine receptor affinity with values below 7 μm. Both these compounds behaved as A1 adenosine receptor antagonists in the performed GTP shift assays. In conclusion, the 2‐benzylidene‐1‐tetralone derivatives can be considered as lead compounds to design a new class of dual acting adenosine A1/A2A receptor antagonists that may have potential in treating both dementia and locomotor deficits in Parkinson's disease.
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