de Costa B R, Mattson M V, George C, Linders J T
Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
J Med Chem. 1992 Dec 11;35(25):4704-12. doi: 10.1021/jm00103a008.
The novel semirigid derivatives (+)-cis-1-[2-phenyl-2-bicyclo[3.1.0]hexyl]piperidine [(+)-8], its enantiomer (-)-8, and (+-)-trans-1-[2-phenyl-2-bicyclo[3.1.0]hexyl]piperidine [(+/-)-9] were synthesized as probes to investigate the mode of interaction of phencyclidine (PCP) with its binding site on the N-methyl-D-aspartate receptor complex. Each target compound was obtained in five steps starting from cyclopent-2-enone. (+)- and (-)-8 were obtained in greater than 98% optical purity through three recrystallizations from ethanol of the (S)-(+)- and (R)-(-)-mandelate salts of intermediate (+-)-cis-2-phenyl-2-bicyclo[3.1.0]hexylamine ([(+/-)-16]. Crystallization of the (R)-(-)-mandelate salt afforded (1R,2R,5S)-(-)-16, whereas the (S)-(+)-mandelate salt afforded (1S,2S,5R)-(+)-16; the absolute configuration was determined by single-crystal X-ray analysis of (-)-16.(R)-(-)-mandelate. Single-crystal X-ray analysis of (+/-)-9-picrate confirmed its trans configuration and provided conformational data. (+)- and (-)-8 and (+/-)-9 were examined for their ability to interact with PCP and sigma binding sites in vitro using [3H]TCP and [3H]pentazocine as radioligands. The binding was compared with that of PCP and contrasted with the rigid symmetrical phencyclidine derivatives cis- and trans-1-[3-phenyl-3-bicyclo[3.1.0]hexyl]piperidines (6 and 7). The results of the study indicated that the conformations of PCP represented by 6-9 are not optimal for potent interaction at either of these sites. Affinities ranged from 582 nM [(+/-)-9] to 29,000 nM [(+)-8] at PCP binding sites and from 1130 nM [(-)-8] to 16,300 nM (7) at sigma sites. In this assay, PCP exhibited affinities of 64.5 nM at PCP and 1090 nM at sigma sites. Qualitative correlation between the sigma and PCP binding data suggests some similarities between these binding sites. An axial phenyl and equatorial piperidine ring with the nitrogen lone pair of electrons antiperiplanar to the phenyl ring has been postulated as the receptor-active conformation of PCP-like ligands at the PCP binding site. Comparison of the binding data of 7-9 with that of the previously described methylcyclohexyl-PCP derivatives allowed its rationalization in terms of this model. It is likely that the lowered affinity in this bicyclo[3.1.0]hexane series is a consequence of nonoptimal geometry (pseudoequatorial phenyl or pseudoboat) for binding as opposed to the presence of steric bulk which proved deleterious in the methylcyclohexyl-PCP derivatives.
合成了新型半刚性衍生物（+）-顺式-1-[2-苯基-2-双环[3.1.0]己基]哌啶[（+）-8]、其对映体（-）-8和（±）-反式-1-[2-苯基-2-双环[3.1.0]己基]哌啶[（±）-9]，作为研究苯环己哌啶（PCP）与其在N-甲基-D-天冬氨酸受体复合物上结合位点相互作用模式的探针。每个目标化合物均从环戊-2-烯酮开始，经五步反应制得。通过对中间体（±）-顺式-2-苯基-2-双环[3.1.0]己胺[（±）-16]的（S）-（+）-和（R）-（-）-扁桃酸盐在乙醇中进行三次重结晶，得到光学纯度大于98%的（+）-和（-）-8。（R）-（-）-扁桃酸盐结晶得到（1R,2R,5S）-（-）-16，而（S）-（+）-扁桃酸盐结晶得到（1S,2S,5R）-（+）-16；绝对构型通过（-）-16·（R）-（-）-扁桃酸盐的单晶X射线分析确定。（±）-9-苦味酸盐的单晶X射线分析证实了其反式构型并提供了构象数据。使用[3H]TCP和[3H]喷他佐辛作为放射性配体，体外检测了（+）-和（-）-8以及（±）-9与PCP和σ结合位点相互作用的能力。将该结合与PCP的结合进行比较，并与刚性对称苯环己哌啶衍生物顺式和反式-1-[3-苯基-3-双环[3.1.0]己基]哌啶（6和7）进行对比。研究结果表明，由6-9代表的PCP构象对于在这两个位点中的任何一个进行有效相互作用都不是最优的。在PCP结合位点的亲和力范围为582 nM[（±）-9]至29000 nM[（+）-8]，在σ位点的亲和力范围为1130 nM[（-）-8]至16300 nM（7）。在该测定中，PCP在PCP结合位点的亲和力为64.5 nM，在σ位点的亲和力为1090 nM。σ和PCP结合数据之间的定性相关性表明这些结合位点之间存在一些相似性。已推测在PCP结合位点，具有与苯环反式共平面的氮孤对电子的轴向苯基和赤道哌啶环是PCP样配体的受体活性构象。将7-9的结合数据与先前描述的甲基环己基-PCP衍生物的结合数据进行比较，可根据该模型对其进行合理化解释。在该双环[3.
