1,3,7-Triethyl-substituted xanthines-possess nanomolar affinity for the adenosine A1 receptor

Adenosine A(1) receptors are attracting great interest as drug targets for their role in cognitive deficits. Antagonism of the adenosine A(1) receptor may offer therapeutic benefits in complex neurological diseases, such as Alzheimer's and Parkinson's disease. The aim of this study was to discover potential selective adenosine A(1) receptor antagonists. Several analogs of 8-(3-phenylpropyl)xanthines (3), 8-(2-phenylethyl)xanthines (4) and 8-(phenoxymethyl) xanthines (5) were synthesized and assessed as antagonists of the adenosine A(1) and A(2A) receptors via radioligand binding assays. The results indicated that the 1,3,7-triethyl-substituted analogs (3d, 4d, and 5d), among each series, displayed the highest affinity for the adenosine A(1) receptor with K-i values in the nanomolar range. This ethyl-substitution pattern was previously unknown to enhance adenosine A(1) receptor binding affinity. The 1,3,7-triethyl-substituted analogs (3d, 4d, and 5d) behaved as adenosine A(1) receptor antagonists in GTP shift assays performed with either rat cortical or whole brain membranes expressing adenosine A(1) receptors. Further, in vivo evaluation of 3d showed reversal of adenosine A(1) receptor agonist-induced hypolocomotion. In conclusion, the most potent evaluated compound, 8-(3-phenylpropyl)-1,3,7-triethylxanthine (3d), showed both in vitro and in vivo activity, and therefore represent a novel adenosine A(1) receptor antagonist that may have potential as a drug candidate for dementia disorders. (c) 2015 Elsevier Ltd. All rights reserved.