Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Hittorfstraße 58-62, D-48149 Münster, Germany.
Bioorg Med Chem. 2010 Nov 15;18(22):7855-67. doi: 10.1016/j.bmc.2010.09.047. Epub 2010 Sep 25.
A series of chiral non-racemic dexoxadrol analogues with various substituents in position 4 of the piperidine ring was synthesized and pharmacologically evaluated. Only the enantiomers having (S)-configuration at the 2-position of the piperidine ring and 4-position of the dioxolane ring were considered. Key steps in the synthesis were an imino-Diels-Alder reaction of enantiomerically pure imine (S)-13, which had been obtained from d-mannitol, with Danishefsky's Diene 14 and the replacement of the p-methoxybenzyl protective group with a Cbz-group. It was shown that (S,S)-configuration of the ring junction (position 2 of the piperidine ring and position 4 of the dioxolane ring) and axial orientation of the C-4-substituent ((4S)-configuration) are crucial for high NMDA receptor affinity. 2-(2,2-Diphenyl-1,3-dioxolan-4-yl)piperidines with a hydroxy moiety ((S,S,S)-5, K(i)=28nM), a fluorine atom ((S,S,S)-6, WMS-2539, K(i)=7nM) and two fluorine atoms ((S,S)-7, K(i)=48nM) in position 4 represent the most potent NMDA antagonists with high selectivity against σ(1) and σ(2) receptors and the polyamine binding site of the NMDA receptor. The NMDA receptor affinities of the new ligands were correlated with their electrostatic potentials, calculated gas phase proton affinities (negative enthalpies of deprotonation) and dipole moments. According to these calculations decreasing proton affinity and increasing dipole moment are correlated with decreasing NMDA receptor affinity.
我们合成了一系列手性非外消旋的德索罗杜尔类似物，这些类似物的哌啶环 4 位具有不同的取代基，并对其进行了药理学评价。只有哌啶环 2 位和二氧戊环 4 位具有（S）构型的对映异构体被认为具有活性。合成过程中的关键步骤是对映体纯亚胺（S）-13 与 Danishefsky 的二烯 14 进行亚胺-Diels-Alder 反应，（S）-13 是由 D-甘露醇衍生而来的，然后将对甲氧苄基保护基替换为 Cbz 基团。研究表明，环连接（哌啶环 2 位和二氧戊环 4 位）的（S，S）构型和 C-4 取代基的轴向取向（（4S）构型）对于高 NMDA 受体亲和力至关重要。具有羟基部分（（S，S，S）-5，K(i)=28nM）、氟原子（（S，S，S）-6，WMS-2539，K(i)=7nM）和两个氟原子（（S，S）-7，K(i)=48nM）的 2-（2,2-二苯基-1,3-二氧戊环-4-基）哌啶是最有效的 NMDA 拮抗剂，对 σ(1)和 σ(2)受体以及 NMDA 受体的聚胺结合位点具有高选择性。新配体的 NMDA 受体亲和力与其静电势、气相质子亲和力（去质子化的负焓）和偶极矩相关。根据这些计算，质子亲和力降低和偶极矩增加与 NMDA 受体亲和力降低相关。
