Thurkauf A, Zenk P C, Balster R L, May E L, George C, Carroll F I, Mascarella S W, Rice K C, Jacobson A E, Mattson M V
Section on Drug Design and Synthesis, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892.
J Med Chem. 1988 Dec;31(12):2257-63. doi: 10.1021/jm00120a004.
Etoxadrol (2a), one of the eight possible optical isomers of 2-ethyl-2-phenyl-4-(2-piperidyl)-1,3-dioxolane, was synthesized from (S,S)-1-(2-piperidyl)-1,2-ethanediol, which was obtained from cleavage of dexoxadrol (1a, (S,S)-2,2-diphenyl-4-(2-piperidyl)-1,3-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 etoxadrol at the C-2 center, was also obtained from the synthesis. This much less potent enantiomer has the 2R,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 phencyclidine site. 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 etoxadrol and the lesser affinity of epietoxadrol for the phencyclidine site.
依托沙朵（2a）是2-乙基-2-苯基-4-（2-哌啶基）-1,3-二氧戊环的八种可能光学异构体之一，它由（S,S）-1-（2-哌啶基）-1,2-乙二醇合成，该二醇是通过右旋沙朵（1a，（S,S）-2,2-二苯基-4-（2-哌啶基）-1,3-二氧戊环）裂解得到的。通过单晶X射线分析确定，具有苯环己哌啶样生物活性的盐酸依托沙朵在其三个手性中心的绝对构型为2S、4S和6S。依托沙朵在C-2中心的差向异构体表依托沙朵（2b）也在合成过程中得到。这种活性低得多的对映体具有2R、4S、6S构型。发现依托沙朵对苯环己哌啶结合位点的亲和力与苯环己哌啶本身相当，且比其差向异构体表依托沙朵强35倍。制备了三种对苯环己哌啶位点亲和力低的非对映体混合物。在对这些化合物辨别刺激特性的研究中，发现只有依托沙朵能替代苯环己哌啶刺激。利用计算机辅助分子建模技术，已开发出一种假设的苯环己哌啶结合位点模型，与我们基于德雷丁模型的先前假设不同，该模型正确预测了依托沙朵对苯环己哌啶位点的较高亲和力和表依托沙朵的较低亲和力。
