2-Benzylidene-1-Indanone Analogues as Dual Adenosine A1/A2a Receptor Antagonists for the Potential Treatment of Neurological Conditions.

Previous studies explored 2-benzylidine-1-tetralone derivatives as innovative adenosine A and A 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 A and A 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 A and A 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 A 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 A receptor antagonist, compound 2 H: . Compound 2C: and the 2Q: behaved as adenosine A 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 A and A receptor antagonists for the potential treatment of neurological conditions.