The adenosine A<sub>2Asub> antagonistic properties of selected C8-substituted xanthines

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• 作者：Mietha M. Van der Walt ; Gisella Terre¡¯Blanche ; An¨¦l Petzer ; Anna C.U. Lourens ; Jacobus P. Petzer
• 关键词：Adenosine A2A receptors ; Antagonism ; Xanthine ; Haloperidol-induced catalepsy ; Parkinson&rsquo ; s disease
• 刊名：Bioorganic Chemistry
• 出版年：2013
• 出版时间：August, 2013
• 年：2013
• 卷：49
• 期：Complete
• 页码：49-58
• 全文大小：734 K

文摘

The adenosine A<sub>2Asub> receptor is considered to be an important target for the development of new therapies for Parkinson¡¯s disease. Several antagonists of the A<sub>2Asub> receptor have entered clinical trials for this purpose and many research groups have initiated programs to develop A<sub>2Asub> receptor antagonists. Most A<sub>2Asub> receptor antagonists belong to two different chemical classes, the xanthine derivatives and the amino-substituted heterocyclic compounds. In an attempt to discover high affinity A<sub>2Asub> receptor antagonists and to further explore the structure-activity relationships (SARs) of A<sub>2Asub> antagonism by the xanthine class of compounds, this study examines the A<sub>2Asub> 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 K<sub>isub> 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 A<sub>2Asub> 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 A<sub>2Asub> receptor.