Synthesis, Stereochemistry, and Biological Activity of the 1-(1-phenyl-2-methylcyclohexyl)piperidines and the 1-(1-phenyl-4-methylcyclohexyl)piperidines. Absolute Configuration of the Potent trans-(-)-1-(1-phenyl-2-methylcyclohexyl)piperidine

J Med Chem. 1991 Aug;34(8):2615-23. doi: 10.1021/jm00112a041.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Brain / metabolism
  • Chemical Phenomena
  • Chemistry
  • Mice
  • Molecular Conformation
  • Molecular Structure
  • Motor Activity / drug effects
  • Phencyclidine / analogs & derivatives*
  • Phencyclidine / chemistry
  • Phencyclidine / metabolism
  • Phencyclidine / pharmacology
  • Rats
  • Structure-Activity Relationship
  • X-Ray Diffraction

Substances

  • 1-(1-phenyl-2-methylcyclohexyl)piperidine
  • Phencyclidine