Synthesis, configuration, and activity of isomeric 2-phenyl-2-(N-piperidinyl)bicyclo[3.1.0]hexanes at phencyclidine and sigma binding sites

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.

MeSH terms

  • Animals
  • Binding Sites / drug effects
  • Brain / drug effects
  • Brain / metabolism
  • Bridged Bicyclo Compounds / chemical synthesis*
  • Guinea Pigs
  • Hexanes / chemical synthesis*
  • Hexanes / metabolism
  • Hexanes / pharmacology
  • Male
  • Models, Molecular
  • Phencyclidine / metabolism*
  • Piperidines / chemical synthesis*
  • Piperidines / metabolism
  • Piperidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / drug effects*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Receptors, Phencyclidine / drug effects*
  • Receptors, Phencyclidine / metabolism
  • Receptors, sigma / drug effects*
  • Receptors, sigma / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship


  • Bridged Bicyclo Compounds
  • Hexanes
  • Piperidines
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Phencyclidine
  • Receptors, sigma
  • Phencyclidine