Brandt W
Institute of Biochemistry, Martin-Luther-University Halle-Wittenberg, Germany.
J Comput Aided Mol Des. 1998 Nov;12(6):615-21. doi: 10.1023/a:1008003421291.
On the basis of a model of the pharmacophore conformations of agonist of the delta-opioid receptor the corresponding delta-antagonist conformations were determined by means of force field calculations. The results explain the unusual behavior of several cyclic beta-casomorphin analogues on the molecular level. Thus, for instance, the model helps to understand why Tyr-c[D-Orn-2-Nal-D-Pro-Gly] is a mixed mu-agonist and delta-antagonist. Furthermore, the model is consistent with low energy conformations of other delta-antagonists such as Tyr-Tic-Phe, Tyr-Tic-Phe-Phe, naltrindole and BNTX. The occupation of a special spatial area by bulky groups close to the protonated N-terminus of opioid peptides is assumed to be highly critical for the switch from agonist to antagonist behavior.
基于δ-阿片受体激动剂药效团构象模型，通过力场计算确定了相应的δ-拮抗剂构象。结果从分子水平解释了几种环β-酪蛋白吗啡类似物的异常行为。例如，该模型有助于理解为什么Tyr-c[D-鸟氨酸-2-萘-D-脯氨酸-甘氨酸]是一种混合μ-激动剂和δ-拮抗剂。此外，该模型与其他δ-拮抗剂如Tyr-Tic-Phe、Tyr-Tic-Phe-Phe、纳曲吲哚和BNTX的低能构象一致。靠近阿片肽质子化N端的大基团占据特殊空间区域被认为对从激动剂行为转变为拮抗剂行为至关重要。
