Aepkers Marion, Wünsch Bernhard
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Hittorfstrasssse 58-62, D-48149 Münster, Germany.
Bioorg Med Chem. 2005 Dec 15;13(24):6836-49. doi: 10.1016/j.bmc.2005.07.030. Epub 2005 Sep 19.
The synthesis and NMDA receptor affinity of ring and side-chain homologues of etoxadrol and dexoxadrol are described. For the regioselective synthesis of etoxadrol homologues, the regioisomeric 4-azidobutanediols (+/-)-9 and (+/-)-14 were employed. A synthesis of the enantiomerically pure azidobutanediols (S)-, (R)-9 and (S)-, (R)-14 was developed and the homochiral building blocks were used for the synthesis of enantiomerically pure etoxadrol and dexoxadrol homologues. The affinity of the racemic and enantiomerically pure primary amines toward the phencyclidine binding site of the NMDA receptor was investigated in receptor binding studies with tritium labeled [3H]-(+)-MK-801 as radioligand. Benzaldehyde derivatives (+/-)-12a, (+/-)-13a, and (+/-)-16a bearing a proton at the acetalic position do not interact significantly with the NMDA receptor. An enantioselective NMDA receptor binding was observed for the trans-configured 2-(2-ethyl-2-phenyl-1,3-dioxolan-4-yl)ethanamine 13b, the (2-ethyl-2-phenyl-1,3-dioxan-4-yl)methanamine 16b, and the (2,2-diphenyl-1,3-dioxan-4-yl)methanamine 16c. The NMDA receptor affinity of these compounds resides almost exclusively in the (S)-configured enantiomers (2S,4S)-13b, (2S,4S)-16b, and (4S)-16c. The lowest Ki-value in this series was found for the (2S,4S)-configured 1,3-dioxolane (2S,4S)-13b (Ki = 69 nM), which is in the range of the Ki-value of the lead compounds etoxadrol and dexoxadrol, indicating that the 2-aminoethyl and the piperidin-2-yl substituents lead to similar NMDA receptor interactions.
描述了依托沙朵和地索沙朵的环同系物及侧链同系物的合成及其对N-甲基-D-天冬氨酸（NMDA）受体的亲和力。为了区域选择性合成依托沙朵同系物，使用了区域异构体4-叠氮基丁二醇（±）-9和（±）-14。开发了对映体纯的叠氮基丁二醇（S）-、（R）-9和（S）-、（R）-14的合成方法，并将这些纯手性结构单元用于对映体纯的依托沙朵和地索沙朵同系物的合成。在以氚标记的[3H]-(+)-MK-801作为放射性配体的受体结合研究中，研究了外消旋和对映体纯的伯胺对NMDA受体苯环利定结合位点的亲和力。在缩醛位置带有质子的苯甲醛衍生物（±）-12a、（±）-13a和（±）-16a与NMDA受体没有明显相互作用。对于反式构型的2-(2-乙基-2-苯基-1,3-二氧戊环-4-基)乙胺13b、(2-乙基-2-苯基-1,3-二氧己环-4-基)甲胺16b和(2,2-二苯基-1,3-二氧己环-4-基)甲胺16c，观察到了对NMDA受体的对映选择性结合。这些化合物对NMDA受体的亲和力几乎完全存在于（S）构型的对映体（2S,4S）-13b、（2S,4S）-16b和（4S）-16c中。在该系列中，发现（2S,4S）构型的1,3-二氧戊环（2S,4S）-13b的最低抑制常数（Ki）值（Ki = 69 nM），该值在先导化合物依托沙朵和地索沙朵的Ki值范围内，表明2-氨基乙基和哌啶-2-基取代基导致类似的NMDA受体相互作用。
