Thurkauf A, de Costa B, Yamaguchi S, Mattson M V, Jacobson A E, Rice K C, Rogawski M A
Laboratory of Medicinal Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, and Medical Neurology Branch, National Institutes of Health, Bethesda, Maryland 20892.
J Med Chem. 1990 May;33(5):1452-8. doi: 10.1021/jm00167a027.
Thirty-eight analogues of 1-phenylcyclohexylamine (PCA), a phencyclidine (PCP) derivative, were examined for their activities in the mouse maximal electroshock (MES) seizure test and in a motor-toxicity assay. In addition, we determined the binding affinities of the compounds for PCP acceptor sites in rat brain membranes labeled with [3H]-1-[1-(2-thienyl)cyclohexyl]piperidine. Many of the analogues were protective against MES seizures (ED50s of 5-41 mg/kg, ip) and all of these compounds caused motor toxicity. The potencies in the motor toxicity and MES seizure tests showed a moderate correlation with the affinities for PCP sites. Several analogues exhibited a greater separation of potencies in the motor toxicity and MES seizure tests than did the parent compound PCA. These were obtained by (i) 3-methylation of the cyclohexyl ring trans to the phenyl ring, (ii) methoxylation at the ortho position on the phenyl ring, and (iii) contraction of the cyclohexane ring to form the corresponding cyclopentane.
对苯环利定（PCP）衍生物1-苯基环己胺（PCA）的38种类似物进行了小鼠最大电休克（MES）惊厥试验和运动毒性测定。此外，我们还测定了这些化合物对用[3H]-1-[1-（2-噻吩基）环己基]哌啶标记的大鼠脑膜中PCP受体位点的结合亲和力。许多类似物对MES惊厥具有保护作用（腹腔注射半数有效剂量为5-41mg/kg），并且所有这些化合物都会引起运动毒性。运动毒性试验和MES惊厥试验中的效价与PCP位点的亲和力呈中度相关。与母体化合物PCA相比，几种类似物在运动毒性试验和MES惊厥试验中的效价分离度更大。这些类似物是通过以下方式获得的：（i）对与苯环反式的环己基环进行3-甲基化，（ii）在苯环的邻位进行甲氧基化，以及（iii）将环己烷环缩合形成相应的环戊烷。
