Synthesis, absolute configuration, and molecular modeling study of etoxadrol, a potent phencyclidine-like agonist.
Synthesis, absolute configuration, and molecular modeling study of etoxadrol, a potent phencyclidine-like agonist.
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强效苯环己哌啶类激动剂依托托醇的合成、绝对构型和分子模型研究。
DOI：
10.1021/jm00120a004
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发表时间：
1988
影响因子：
7.3
通讯作者：
Mattson,MV
中科院分区：
文献类型：
--
作者：
Thurkauf,A;Zenk,PC;Balster,RL;May,EL;George,C;Carroll,FI;Mascarella,SW;Rice,KC;Jacobson,AE;Mattson,MV
乙氧沙卓（2a）是2-乙基-2-苯基-4-（2-哌啶基）-1，3-二氧戊环的八种可能的光学异构体之一，由右氧沙卓（1a，（S，S）-2，2-二苯基-4-（2-哌啶基）-1，3-二氧戊环）裂解得到的（S，S）-1-（2-哌啶基）-1，2-乙烷合成。盐酸乙氧沙德罗是一种苯环利定类化合物，通过单晶X-射线衍射分析确定其三个手性中心的绝对构型为2S、4S和6S。在C-2中心与乙氧沙醇差向异构的表氧沙醇（2b）也从合成中获得。这种效力低得多的对映异构体具有2 H，4S，6S构型。发现乙氧沙德罗对苯环利定结合位点的亲和力与苯环利定本身的亲和力相当，并且比其差向异构体表乙氧沙德罗的效力高35倍。制备了三种对苯环己哌啶具有低亲和力的非对映体混合物。在对这些化合物的辨别刺激特性的研究中，发现只有乙氧沙醇替代苯环利定刺激。利用计算机辅助分子模拟技术，一个假设的苯环己哌啶结合位点模型已经开发出来，不像我们以前的假设的基础上Dreiding模型，正确地预测较高的亲和力etoxadrol和较低的亲和力epietoxadrol的苯环己哌啶网站。
Etoxadrol (2a), one of the eight possible optical isomers of 2-ethyl-2-phenyl-4-(2-piperidyl)-l, 3-dioxolane, was synthesized from (S, S)-l-(2-piperidyl)-l, 2-ethanediol, which was obtained from cleavage of dexoxadrol (la,(S, S)-2, 2-di-phenyl-4-(2-piperidyl)-l, 3-dioxolane). The absolute configuration of etoxadrol hydrochloride, a phencyclidine-like compound biologically, was determined to be 2S, 4S, and 6S at its three chiral centers by single-crystal X-ray analysis. Epietoxadrol (2b), epimeric with etoxadrolat the C-2 center, was also obtained from the synthesis. This much less potent enantiomer has the 2fi, 4S, 6S configuration. The affinity of etoxadrol to the phencyclidine binding site was found to be comparable to that of phencyclidine itself and was 35 times more potent than its epimer, epietoxadrol. Three diastereomeric mixtures were prepared that had low affinity for the phencyclidinesite. In studies of the discriminative stimulus properties of these compounds, it was found that only etoxadrol substituted for the phencyclidine stimulus. With use of computer-assisted molecular modeling techniques, a hypothetical phencyclidine binding site model has been developed that, unlike our former hypothesis based on Dreiding models, correctly predicts the higher affinity of etoxadroland the lesser affinity of epietoxadrol for the phencyclidine site.