Evaluation of 2-benzylidene-1-tetralone derivatives as antagonists of A1 and A2A adenosine receptors

Abstract

Antagonists of the adenosine receptors (A₁ and A_2A) 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 A_2A 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 A_2A adenosine receptor. The 2-benzylidene-1-tetralones bearing a hydroxyl substituent at either position C5, C6 or C7 of ring A displayed favorable adenosine A₁ receptor binding, while C5 hydroxy substitution led to favorable A_2A 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 A_2A adenosine receptor affinity. Compounds 4 and 8 displayed the highest A₁ and A_2A adenosine receptor affinity with values below 7μM. 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/A_2A receptor antagonists that may have potential in treating both dementia and locomotor deficits in Parkinson's disease.

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Substitution of 2-benzylidene-1-tetralone with a hydroxy group on ring A and/or B played a key role in modulating the binding affinity and selectivity for the adenosine A₁ and A_2A receptors. Generally, C5-hydroxy substitution on ring A favored A₁ affinity, while C4′-hydroxy substitution on ring B governed both A₁ and A_2A affinity. Adenosine A₁ and A_2A receptor antagonists are deemed therapeutically beneficial in Parkinson's disease; thus, 2-benzylidene-1-tetralones represent a new class of dual acting adenosine A₁ and A_2A receptor antagonists.

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