5 years ago

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

Evaluation of 2-benzylidene-1-tetralone derivatives as antagonists of A1 and A2A adenosine receptors
Mietha M. Van der Walt, Gisella Terre'Blanche, Lesetja J. Legoabe
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 favorable adenosine A1 receptor binding, while C5 hydroxy substitution led to favorable 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 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/A2A receptor antagonists that may have potential in treating both dementia and locomotor deficits in Parkinson's disease. This article is protected by copyright. All rights reserved. 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 A2A receptors. Generally, C5-hydroxy substitution on ring A favored A1 affinity, while C4′-hydroxy substitution on ring B governed both A1 and A2A affinity. Adenosine A1 and A2A 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 A2A receptor antagonists.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.13074

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