de Costa B R, George C, Burke T R, Rafferty M F, Contreras P C, Mick S J, Jacobson A E, Rice K C
Section on Drug Design and Synthesis, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892.
J Med Chem. 1988 Aug;31(8):1571-5. doi: 10.1021/jm00403a014.
Brown oxidation of cis-bicyclo[3.1.0]hexan-3-ol afforded bicyclo[3.1.0]hexan-3-one in 98% yield. Treatment of this ketone with either phenyllithium or phenylamagnesium bromide in ether at room temperature followed by solvolysis of the resulting alcohol in a mixture of trifluoroacetic acid, sodium azide, and chloroform gave a mixture of cis- and trans-3-azido-3-phenylbicyclo[3.1.0]hexanes. LAH reduction of this crude mixture of azides afforded a 1:3.5 mixture of cis- and trans-3-phenyl-3-bicyclo[3.1.0]hexylamine, respectively, in 51% overall yield from the alcohol. Separation of the mixture of amines by column chromatography followed by cyclization of each by heating at 60 degrees C in DMF solution with 1 equiv of 1,5-dibromopentane furnished the two conformationally restrained analogues of phencyclidine (PCP), cis- and trans-3-phenyl-3-piperidinylbicyclo[3.1.0]hexane (1 and 2, respectively), in high yield. Configurations were assigned on the basis of an X-ray crystallographic analysis of the cis isomer (1). Bond lengths and angles are similar to those found in PCP and its derivatives. Binding to PCP receptors and sigma sites as well as behavioral effects of 1 and 2 in rats was determined relative to PCP. In displacement of specifically bound [3H]TCP (1-[1-(2-thienyl)cyclohexyl]piperidine) from PCP receptors, 1 and 2 were nearly equipotent and about one-seventh as potent as PCP. These compounds were about one-fifth as potent as PCP in displacing [3H]-(+)-SKF 10,047 from its binding site. Calculation of the ED50 values of 1 and 2 for stereotyped behavior and ataxia indicated that they were about equipotent, and 2-3-fold less active than PCP.
顺式双环[3.1.0]己烷-3-醇经布朗氧化反应生成双环[3.1.0]己烷-3-酮，产率为98%。在室温下，将该酮与苯基锂或苯基溴化镁在乙醚中反应，然后将所得醇在三氟乙酸、叠氮化钠和氯仿的混合物中进行溶剂解，得到顺式和反式-3-叠氮基-3-苯基双环[3.1.0]己烷的混合物。用氢化铝锂还原该叠氮化物的粗混合物，分别得到顺式和反式-3-苯基-3-双环[3.1.0]己胺的1:3.5混合物，以醇为原料计算，总产率为51%。通过柱色谱法分离胺混合物，然后将每种胺在60℃下于二甲基甲酰胺溶液中与1当量的1,5-二溴戊烷加热环化，得到苯环己哌啶（PCP）的两种构象受限类似物，顺式和反式-3-苯基-3-哌啶基双环[3.1.0]己烷（分别为1和2），产率很高。根据顺式异构体（1）的X射线晶体学分析确定了构型。键长和键角与PCP及其衍生物中的相似。相对于PCP，测定了1和2与PCP受体和σ位点的结合以及在大鼠中的行为效应。在从PCP受体上置换特异性结合的[3H]TCP（1-[1-(2-噻吩基)环己基]哌啶）时，1和2几乎具有同等效力，效力约为PCP的七分之一。在从其结合位点置换[3H]-(+)-SKF 10,047时，这些化合物的效力约为PCP的五分之一。计算1和2对刻板行为和共济失调的半数有效剂量（ED50）值表明它们几乎具有同等效力，活性比PCP低2至3倍。
