Lamotte-Brasseur J, Dive G, Lamouri A, Heymans F, Godfroid J J
Laboratoire de Microbiologie, Institut de Chimie, Liège, Belgium.
Biochim Biophys Acta. 1991 Aug 20;1085(1):91-105. doi: 10.1016/0005-2760(91)90236-b.
In order to compare electronic and conformational properties of PAF-agonists and PAF-antagonists, 14 analogues structurally related to PAF were studied. A common conformation of the glycerol backbone was present in all agonists and all constrained or flexible antagonists. The distinction between agonists and antagonists appears to be casted on position-2 where the folded conformation of the substituent for agonists should be the most probable. In position-3 the gauche conformation can be adopted by all the analysed compounds. The electrostatic potential well at -30 kcal/mol stretches to the carbonyl group in position-2 in the folded conformation of the agonists. On the contrary, in constrained antagonists, a second negative zone appears around the carbamate group. Given the modelling results, the triethylammonium PAF analogue considered in literature as a weak agonist, was resynthesized and proved to be more potent than previously reported. These experimental results confirm our hypothesis in terms of a common conformation of agonist and antagonist PAF-like molecules.
为了比较血小板活化因子（PAF）激动剂和PAF拮抗剂的电子性质和构象性质，研究了14种与PAF结构相关的类似物。所有激动剂以及所有受限或柔性拮抗剂中甘油主链都存在一种共同构象。激动剂和拮抗剂之间的区别似乎体现在2位，激动剂取代基的折叠构象在该位置应该是最可能的。在3位，所有分析的化合物都可以采用 gauche 构象。在激动剂的折叠构象中，-30 kcal/mol 的静电势阱延伸到2位的羰基。相反，在受限拮抗剂中，氨基甲酸酯基团周围出现第二个负电区域。根据建模结果，文献中认为是弱激动剂的三乙铵PAF类似物被重新合成，并且证明其效力比先前报道的更强。这些实验结果在PAF样激动剂和拮抗剂分子的共同构象方面证实了我们的假设。
