Thurkauf A, Mattson M V, Huguenin P N, Rice K C, Jacobson A E
Section on Drug Design and Synthesis, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, MD 20892.
FEBS Lett. 1988 Oct 10;238(2):369-74. doi: 10.1016/0014-5793(88)80514-3.
Etoxadrol-meta-isothiocyanate (2S,4S,6S-2-ethyl-2-(3-isothiocyanatophenyl)-2-piperidyl)1,3-dioxolane, 4a) has been synthesized and characterized as an irreversible ligand for the phencyclidine (PCP)-binding site. It is the first chiral electrophilic affinity ligand for this site to have been described. This affinity ligand is based upon etoxadrol, a 1,3-dioxolane known to have PCP-like effects in vivo and in vitro. Etoxadrol-meta-isothiocyanate was found to be four-five times more potent in vitro than metaphit (1-[1-(3- isothiocyanatophenyl)cyclohexyl]piperidine), the only previously known electrophilic affinity ligand for the PCP-binding site. The binding was shown to be highly enantioselective for etoxadrol-meta-isothiocyanate (4a). The 2R,4R,6R-enantiomer of 4a was essentially inactive. The ability of the 2S,4S,6S-enantiomer (4a) to interact with the benzodiazepine, muscarinic, and mu opioid receptor systems was also examined, and it was found not to interact with these receptor systems. It seems likely that 4a will prove to be a valuable tool in the study of structure and function of the PCP-binding site.
依托沙朵-间位异硫氰酸酯（(2S,4S,6S)-2-乙基-2-(3-异硫氰酸苯酯基)-2-哌啶基）1,3-二氧戊环，4a）已被合成并表征为苯环己哌啶（PCP）结合位点的不可逆配体。它是首个被描述的针对该位点的手性亲电亲和配体。这种亲和配体基于依托沙朵，一种已知在体内和体外具有类似PCP效应的1,3-二氧戊环。发现依托沙朵-间位异硫氰酸酯在体外的效力比间甲硫哒嗪（1-[1-(3-异硫氰酸苯酯基)环己基]哌啶）高4至5倍，间甲硫哒嗪是之前唯一已知的针对PCP结合位点的亲电亲和配体。已证明依托沙朵-间位异硫氰酸酯（4a）的结合具有高度对映选择性。4a的2R,4R,6R对映体基本无活性。还研究了2S,4S,6S对映体（4a）与苯二氮䓬、毒蕈碱和μ阿片受体系统相互作用的能力，发现它不与这些受体系统相互作用。4a似乎有望成为研究PCP结合位点结构与功能的有价值工具。
