Tetrahydropyrazino-annelated theophylline (1,3-dimethylxanthine) derivatives have previously been shown to display increased water-solubility as compared to the parent xanthines due to their basic character. In the present study, we modified this promising scaffold by replacing the 1,3-dimethyl residues by a variety of alkyl groups including combinations of different substituents in both positions. Substituted benzyl or phenethyl residues were attached to the N8 of the resulting 1,3-dialkyl-tetrahydropyrazino[2,1-f ]purinediones with the aim to obtain multi-target drugs that block human A1 and A2A adenosine receptors (ARs) and monoaminoxidase B (MAO-B). 1,3-Diethyl-substituted derivatives showed high affinity for A1 ARs, e.g., 15d (PSB-18339, 8-m-bromobenzyl-substituted) displayed a Ki value of 13.6 nM combined with high selectivity. 1-Ethyl-3-propargyl-substituted derivatives exhibited increased A2A AR affinity. The 8-phenethyl derivative 20h was selective for the A2A AR (Ki 149 nM), while the corresponding 8-benzyl-substituted compound 20e (PSB-1869) blocked A1 and A2A ARs with equal potency (Ki A1, 180 nM; A2A, 282 nM). The 1-ethyl-3-methyl-substituted derivative 16a (PSB-18405) bearing a m,p-dichlorobenzyl residue at N8 blocked all three targets, A1 ARs (Ki 396 nM), A2A ARs (Ki 1,620 nM), and MAO-B (IC50 106 nM) with high selectivity vs. the other subtypes (A2B and A3 ARs, MAO-A), and can thus be considered as a multi-target drug. Our findings were rationalized by molecular docking studies based on previously published X-ray structures of the protein targets. The new drugs have potential for the treatment of neurodegenerative diseases, in particular Parkinson's disease.

中文翻译：

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在1位和3位上检测取代基：四氢吡喃并环化的水溶性黄嘌呤衍生物作为具有强腺苷受体拮抗活性的多目标药物。

四氢吡嗪基退火的茶碱（1,3-二甲基黄嘌呤）衍生物由于其基本特性，与亲本黄嘌呤相比，先前显示出更高的水溶性。在本研究中，我们通过用各种烷基取代1,3-二甲基残基（包括两个位置上不同取代基的组合）来修饰这种有前途的支架。取代的苄基或苯乙基残基连接到所得的1,3-二烷基-四氢吡嗪并[2,1-f]嘌呤二酮的N8上，目的是获得能阻断人A1和A2A腺苷受体（ARs）和单胺氧化酶的多靶点药物B（MAO-B）。1,3-二乙基取代的衍生物显示出对A1 AR的高度亲和力，例如15d（PSB-18339，8-m-溴苄基取代）显示出13.6 nM的Ki值和高选择性。1-乙基-3-炔丙基取代的衍生物表现出增加的A2A AR亲和力。8-苯乙基衍生物20h对A2A AR（Ki 149 nM）具有选择性，而相应的8-苄基取代的化合物20e（PSB-1869）则以相同的效价（Ki A1，180 nM; A2A， 282 nM）。在N8处带有am，p-二氯苄基残基的1-乙基-3-甲基取代的衍生物16a（PSB-18405）阻断了所有三个靶标，即A1 ARs（Ki 396 nM），A2A ARs（Ki 1,620 nM）和MAO- B（IC50 106 nM）与其他亚型（A2B和A3 ARs，MAO-A）相比具有很高的选择性，因此可以被视为多靶点药物。我们的发现通过基于先前发布的蛋白质靶标的X射线结构的分子对接研究得到了合理化。新药具有治疗神经退行性疾病的潜力，尤其是帕金森氏症。