Van der Walt Mietha M, Terre'Blanche Gisella, Petzer Anél, Lourens Anna C U, Petzer Jacobus P
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Bioorg Chem. 2013 Aug;49:49-58. doi: 10.1016/j.bioorg.2013.06.006. Epub 2013 Jul 4.
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.
腺苷A2A受体被认为是开发帕金森病新疗法的重要靶点。为此，几种A2A受体拮抗剂已进入临床试验阶段，许多研究小组也已启动开发A2A受体拮抗剂的项目。大多数A2A受体拮抗剂属于两种不同的化学类别，即黄嘌呤衍生物和氨基取代杂环化合物。为了发现高亲和力的A2A受体拮抗剂，并进一步探索黄嘌呤类化合物对A2A拮抗作用的构效关系（SARs），本研究考察了一系列（E）-8-苯乙烯基黄嘌呤、8-（苯氧甲基）黄嘌呤和8-（3-苯丙基）黄嘌呤的A2A拮抗特性。结果表明，在这些系列中，（E）-8-苯乙烯基黄嘌呤具有最高的结合亲和力，其中最有效的同系物（E）-1,3-二乙基-7-甲基-8-[(3-三氟甲基)苯乙烯基]黄嘌呤的Ki值为11.9 nM。该化合物还能有效逆转氟哌啶醇诱导的大鼠僵住症，证明它实际上是一种A2A受体拮抗剂。8-（苯氧甲基）黄嘌呤和8-（3-苯丙基）黄嘌呤对A2A受体均未表现出高结合亲和力，这一发现证明了C8位被苯乙烯基部分取代的重要性。
