5-Substituted 2-benzylidene-1-tetralone analogues as A1 and/or A2A antagonists for the potential treatment of neurological conditions

• Published in: Bioorganic chemistry 2017-10, Vol.74, p.251-259
• Main Authors: Janse van Rensburg, H.D., Terre'Blanche, G., van der Walt, M.M., Legoabe, L.J.
• Format: Article
• Language: English
• Subjects: 5-Hydroxy-2-benzylidene-1-tetralones; A1 adenosine receptor antagonists; A2A adenosine receptor antagonists; Alzheimer’s disease; Parkinson’s disease
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2017.08.013

[Display omitted] •A1/A2A receptors are drug targets for Alzheimer’s and Parkinson’s disease.•Novel 5-substitued 2-benzylidene-1-tetralones were synthesized.•Selected 5-substitued 2-benzylidene-1-tetralones possess A1 and A2A affinity. Adenosine A1 and A2A receptors are attracting great interest as drug targets for their role in cognitive and motor deficits, respectively. Antagonism of both these adenosine receptors may offer therapeutic benefits in complex neurological diseases, such as Alzheimer’s and Parkinson’s disease. The aim of this study was to explore the affinity and selectivity of 2-benzylidene-1-tetralone derivatives as adenosine A1 and A2A receptor antagonists. Several 5-hydroxy substituted 2-benzylidene-1-tetralone analogues with substituents on ring B were synthesized and assessed as antagonists of the adenosine A1 and A2A receptors via radioligand binding assays. The results indicated that hydroxy substitution in the meta and para position of phenyl ring B, displayed the highest selectivity and affinity for the adenosine A1 receptor with Ki values in the low micromolar range. Replacement of ring B with a 2-amino-pyrimidine moiety led to compound 12 with an increase of affinity and selectivity for the adenosine A2A receptor. These substitution patterns led to enhanced adenosine A1 and A2A receptor binding affinity. The para-substituted 5-hydroxy analogue 3 behaved as an adenosine A1 receptor antagonists in a GTP shift assay performed with rat whole brain membranes expressing adenosine A1 receptors. In conclusion, compounds 3 and 12, showed the best adenosine A1 and A2A receptor affinity respectively, and therefore represent novel adenosine receptor antagonists that may have potential with further structural modifications as drug candidates for neurological disorders.