van der Wenden E M, Ijzerman A P, Soudijn W
Center for Bio-Pharmaceutical Sciences, Division of Medicinal Chemistry, Leiden, The Netherlands.
J Med Chem. 1992 Feb 21;35(4):629-35. doi: 10.1021/jm00082a003.
Several models have been described in the literature to explain the similarity of interaction of adenosine receptor agonists and antagonists with the binding site of the receptor. Besides the superposition of the nitrogen atoms of adenosine and xanthine (the "standard" model), two other models have been described: one in which xanthine is rotated around its "horizontal" axis before superposition ("flipped") and one in which the adenosine N6-region and the xanthine C8-region are superimposed ("N6-C8"). In this study we compared the steric and electrostatic properties of these models. The flipped model tends to show higher percentages of overlap for the positive electrostatic potentials and the N6-C8 model yielded predominantly a slightly higher overlap for the negative electrostatic potentials, although these differences were rather small. Since the N6-region in adenosine and the C8-region in xanthine are coinciding in this model, the N6-C8 model yielded a much larger overlap in van der Waals volume than the other two models. The N6-C8 model seems therefore to be the more probable model, also because the interactive groups point in the same direction for both adenosine and xanthine analogues. We determined the geometries of both the adenosine N6-substituents and the xanthine 8-substituents in earlier studies. The N6-C8 model causes a coincidence of these separately determined conformations.
文献中描述了几种模型来解释腺苷受体激动剂和拮抗剂与受体结合位点相互作用的相似性。除了腺苷和黄嘌呤氮原子的叠加（“标准”模型）外，还描述了另外两种模型：一种是黄嘌呤在叠加前绕其“水平”轴旋转（“翻转”）的模型，另一种是腺苷N6区域和黄嘌呤C8区域叠加（“N6-C8”）的模型。在本研究中，我们比较了这些模型的空间和静电性质。翻转模型倾向于显示正静电势的重叠百分比更高，而N6-C8模型主要产生负静电势的重叠略高，尽管这些差异相当小。由于在该模型中腺苷的N6区域和黄嘌呤的C8区域重合，N6-C8模型在范德华体积上的重叠比其他两个模型大得多。因此，N6-C8模型似乎是更有可能的模型，这也是因为对于腺苷和黄嘌呤类似物，相互作用基团指向相同的方向。我们在早期研究中确定了腺苷N6取代基和黄嘌呤8取代基的几何结构。N6-C8模型导致这些分别确定的构象重合。
