The adenosine A2A antagonistic properties of selected C8-substituted xanthines
Date
2013Author
Van der Walt, Mietha M.
Terre’Blanche, Gisella
Petzer, Anél
Lourens, Anna C.U.
Petzer, Jacobus P.
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Show full item recordAbstract
The adenosine A2A receptor is considered to be an important target for the development of new therapies
for Parkinson’s disease. Several antagonists of the A2A receptor have entered clinical trials for this purpose
and many research groups have initiated programs to develop A2A receptor antagonists. Most A2A receptor
antagonists belong to two different chemical classes, the xanthine derivatives and the amino-substituted
heterocyclic compounds. In an attempt to discover high affinity A2A receptor antagonists and to
further explore the structure–activity relationships (SARs) of A2A antagonism by the xanthine class of
compounds, this study examines the A2A antagonistic properties of series of (E)-8-styrylxanthines, 8-
(phenoxymethyl)xanthines and 8-(3-phenylpropyl)xanthines. The results document that among these
series, the (E)-8-styrylxanthines have the highest binding affinities with the most potent homologue,
(E)-1,3-diethyl-7-methyl-8-[(3-trifluoromethyl)styryl]xanthine, exhibiting a Ki value of 11.9 nM. This
compound was also effective in reversing haloperidol-induced catalepsy in rats, providing evidence that
it is in fact an A2A receptor antagonist. The importance of substitution at C8 with the styryl moiety was
demonstrated by the finding that none of the 8-(phenoxymethyl)xanthines and 8-(3-phenylpropyl)
xanthines exhibited high binding affinities for the A2A receptor.
URI
http://hdl.handle.net/10394/13695https://www.sciencedirect.com/science/article/pii/S0045206813000230
https://doi.org/10.1016/j.bioorg.2013.06.006
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- Faculty of Health Sciences [2376]