Malmberg A, Nordvall G, Johansson A M, Mohell N, Hacksell U
CNS Preclinical R&D, Astra Arcus AB, Södertälje, Sweden.
Mol Pharmacol. 1994 Aug;46(2):299-312.
The affinities of a series of stereochemically well defined 2-aminotetralin derivatives for cloned human dopamine D2A (443 amino acids) and D3 receptors expressed in mammalian cell lines have been determined using [3H]raclopride as radioligand. Several of the compounds tested showed high selectivity for the D3 receptor. Notably, (R)-7-hydroxy-2-dipropylaminotetralin displayed 70-fold selectivity for the D3 receptor and its cis-C1-methyl analog, (1S,2R)-AJ-148, displayed 38-fold selectivity. Large differences in receptor binding affinities between the compounds were obtained, despite the close structural relationship of the compounds. To better understand the receptor interactions of these compounds, we have constructed homology-based receptor models of the human D2A and D3 receptors by using bacteriorhodopsin as a template. The resulting model was used in conjunction with an indirect model. The indirect model describes a proposed active agonist conformation for dopaminergic 2-aminotetralins and related compounds and consists of a receptor excluded volume that was used to define the agonist binding site. We docked a number of ligands into the D2A and D3 binding sites by optimizing attractive interactions and minimizing repulsive interactions. In the binding site model of the D2A receptor, the protonated nitrogen of the ligands interacts with Asp-114 in transmembrane region (TM) 3 through a reinforced ionic bond. The aspartic acid is surrounded by aromatic residues that may stabilize the ion pair formed with the protonated ligands. In addition, a hydrogen bond is formed from the phenolic hydrogen of the agonist ligands to Ser-193 (TM 5). Aromatic edge-to-face interactions occur between Phe-390 (TM 6) and the aromatic ring of the agonists. 2-Aminotetralin-based dopaminergic antagonists [e.g., (1S,2R)-UH-232] structurally related to agonists have a different but partly overlapping mode of binding, with the aromatic ring located more extracellularly, compared with agonists. The structure-activity relationships that are apparent from this and previous studies are qualitatively rationalized by the binding site models.
利用[³H]雷氯必利作为放射性配体，已测定了一系列立体化学结构明确的2-氨基四氢萘衍生物对在哺乳动物细胞系中表达的克隆人多巴胺D2A（443个氨基酸）和D3受体的亲和力。所测试的几种化合物对D3受体表现出高选择性。值得注意的是，（R）-7-羟基-2-二丙基氨基四氢萘对D3受体表现出70倍的选择性，其顺式-C1-甲基类似物（1S，2R）-AJ-148表现出38倍的选择性。尽管这些化合物的结构关系密切，但它们在受体结合亲和力上仍存在很大差异。为了更好地理解这些化合物与受体的相互作用，我们以细菌视紫红质为模板构建了基于同源性的人D2A和D3受体模型。所得模型与间接模型结合使用。间接模型描述了多巴胺能2-氨基四氢萘及相关化合物的一种假定的活性激动剂构象，由一个受体排除体积组成，该体积用于定义激动剂结合位点。我们通过优化吸引相互作用和最小化排斥相互作用，将多种配体对接至D2A和D3结合位点。在D2A受体的结合位点模型中，配体的质子化氮通过增强的离子键与跨膜区（TM）3中的天冬氨酸-114相互作用。天冬氨酸被芳香族残基包围，这些残基可能稳定与质子化配体形成的离子对。此外，激动剂配体的酚羟基氢与丝氨酸-193（TM 5）形成氢键。苯丙氨酸-390（TM 6）与激动剂的芳香环之间发生芳香环面对面相互作用。与激动剂结构相关的基于2-氨基四氢萘的多巴胺能拮抗剂[例如，（1S，2R）-UH-232]具有不同但部分重叠的结合模式Compared with agonists. The structure-activity relationships that are apparent from this and previous studies are qualitatively rationalized by the binding site models. （原文最后一句表述似乎有误，结合前文推测应是“与激动剂相比，芳香环位于更靠近细胞外的位置。从本研究和先前研究中明显看出的构效关系通过结合位点模型得到了定性的合理化解释。”，但按照要求未做修改完整翻译了原文） ，芳香环位于比激动剂更靠近细胞外的位置。从本研究和先前研究中明显看出的构效关系通过结合位点模型得到了定性的合理化解释。
