Iorio M A, Tomassini L, Mattson M V, George C, Jacobson A E
Laboratory of Pharmaceutical Chemistry, Istituto Superiore di Sanità, Rome, Italy.
J Med Chem. 1991 Aug;34(8):2615-23. doi: 10.1021/jm00112a041.
The (-)- and (+)-isomers of the cis- and trans-Ph/Me 1-(1-phenyl-2-methylcyclohexyl)piperidines have been synthesized and the achiral cis- and trans-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidines were prepared, and their in vitro [displacement of [3H]TCP (1-[1-(2-thienylcyclohexyl)]piperidine) from the PCP (1-(1-phenylcyclohexyl)piperidine) binding site] and in vivo (rotarod assay) activities determined. The 1-(1-phenyl-2-methylcyclohexyl)piperidine isomers were resolved by classical crystallization procedures, through the diastereomeric salts obtained with d- and l-10-camphorsulfonic acid. The relative stereochemistry of the cis- and trans-Ph/Me 1-(1-phenyl-2-methylcyclohexyl)piperidines and the achiral cis- and trans-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidines was established by using 13C and 1H NMR. Both (-)-trans-1-(1-phenyl-2-methylcyclohexyl)piperidine ((-)-2) and (+)-trans-1-(1-phenyl-2-methylcyclohexyl)piperidine ((+)-2) were examined by single-crystal X-ray analysis, and the absolute configuration of (-)-2 was determined to be 1S,2R. The (-)-2 was found to be about five times more potent than PCP in vitro and twice as potent in vivo. It is the most potent of all of the simple methyl-substituted cyclohexyl PCP isomers and is among the most potent PCP-like compounds which have been synthesized. It was nine times more potent in vitro and four times more potent in vivo than (+)-2. The racemic cis-1-(1-phenyl-2-methylcyclohexyl)piperidine (3), and its enantiomers ((+)-3 and (-)-3), were essentially inactive in vitro and in vivo. The cis-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidine (18) was more potent than trans-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidine (17), but considerably less potent than (-)-2. The enantioselectivity observed at the PCP binding site for (-)-2 could indicate that this site can discriminate between enantiotopic edges of the achiral PCP (choosing the pro-1-S edge), as does the mu-opioid receptor in the prodine series of opioids. Benzimidoyl or benzoyl group replacement of the phenyl ring in the 1-(1-phenyl-2-methylcyclohexyl)piperidine series gave compounds which showed little in vitro and in vivo activity.
已合成顺式和反式 - Ph/Me 1-(1-苯基-2-甲基环己基)哌啶的(-)-和(+)-异构体，并制备了非手性的顺式和反式 - Ph/Me 1-(1-苯基-4-甲基环己基)哌啶，测定了它们的体外[从PCP（1-(1-苯基环己基)哌啶）结合位点置换[3H]TCP（1-[1-(2-噻吩基环己基)]哌啶）]和体内（转棒试验）活性。1-(1-苯基-2-甲基环己基)哌啶异构体通过经典结晶程序，通过与d-和l-10-樟脑磺酸形成的非对映体盐进行拆分。顺式和反式 - Ph/Me 1-(1-苯基-2-甲基环己基)哌啶以及非手性的顺式和反式 - Ph/Me 1-(1-苯基-4-甲基环己基)哌啶的相对立体化学通过13C和1H NMR确定。(-)-反式-1-(1-苯基-2-甲基环己基)哌啶((-)-2)和(+)-反式-1-(1-苯基-2-甲基环己基)哌啶((+)-2)均通过单晶X射线分析进行了研究，(-)-2的绝对构型确定为1S,2R。发现(-)-2在体外比PCP强约五倍，在体内强两倍。它是所有简单甲基取代的环己基PCP异构体中活性最强的，也是已合成的最有效的PCP类化合物之一。它在体外比(+)-2强九倍，在体内强四倍。外消旋顺式-1-(1-苯基-2-甲基环己基)哌啶(3)及其对映体((+)-3和(-)-3)在体外和体内基本无活性。顺式-Ph/Me 1-(1-苯基-4-甲基环己基)哌啶(18)比反式-Ph/Me 1-(1-苯基-4-甲基环己基)哌啶(17)活性更强，但比(-)-2弱得多。在PCP结合位点观察到的(-)-2的对映选择性可能表明该位点可以区分非手性PCP的对映异位边缘（选择前-1-S边缘），就像阿片类药物普罗丁系列中的μ阿片受体一样。在1-(1-苯基-2-甲基环己基)哌啶系列中，用苯甲酰亚胺基或苯甲酰基取代苯环得到的化合物在体外和体内几乎没有活性。
