2–Benzylidene–1–Indanone Analogues as Dual Adenosine A₁/A_2a Receptor Antagonists for the Potential Treatment of Neurological Conditions

Abstract

Previous studies explored 2-benzylidine-1-tetralone derivatives as innovative adenosine A₁ and A_2A 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 A_2A 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 A_2A 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 A_2A 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 A_2A receptor antagonists for the potential treatment of neurological conditions.

Key words

parkinson’s disease - alzheimer’s disease - 4–hydroxy–2–benzylidene–1–indanones - adenosine antagonists

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