Synthesis and resolution of cis-(+/-)-methyl (1R,2S/1S,2R)-2-[(4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl)cyclopropanecarboxylate [(+/-)-PPCC)]: new sigma receptor ligands with neuroprotective effect

J Med Chem. 2010 Aug 12;53(15):5881-5. doi: 10.1021/jm100116p.

Abstract

The enantiomers of cis-(+/-)-methyl (1R,2S/1S,2R)-2-[(4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl)cyclopropanecarboxylate [1, (+/-)-PPCC], a selective sigma ligand, were synthesized. The (+)- and (-)-enantiomers bind predominantly to sigma(1) receptors and have a reduced sigma(2) affinity. Both individually restore the astroglial oxidative status modified by glutamate, counteracting also transglutaminase-2 overexpression. They exhibited in vivo anti-opioid effects on kappa opioid (KOP) receptor-mediated analgesia. Our findings demonstrate that the enantiomers display mainly sigma(1) agonist activity and that they have neuroprotective effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / pharmacology
  • Analgesics, Non-Narcotic / pharmacology
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Cells, Cultured
  • Cyclopropanes / chemical synthesis*
  • Cyclopropanes / chemistry
  • Cyclopropanes / pharmacology
  • Drug Interactions
  • GTP-Binding Proteins / biosynthesis
  • Glutamic Acid / pharmacology
  • Glutathione / metabolism
  • Ibogaine / pharmacology
  • Ligands
  • Neuroprotective Agents / chemical synthesis*
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology
  • Oxidative Stress
  • Pentazocine / pharmacology
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacology
  • Protein Glutamine gamma Glutamyltransferase 2
  • Rats
  • Reactive Oxygen Species / metabolism
  • Receptors, Opioid, kappa / agonists
  • Receptors, sigma / agonists*
  • Receptors, sigma / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Transglutaminases / biosynthesis

Substances

  • Analgesics, Non-Narcotic
  • Cyclopropanes
  • Ligands
  • Neuroprotective Agents
  • Piperidines
  • Reactive Oxygen Species
  • Receptors, Opioid, kappa
  • Receptors, sigma
  • Tgm2 protein, rat
  • methyl 2-((4-hydroxy-4-phenylpiperidin-1-yl)methyl)-1-(4-methylphenyl)cyclopropanecarboxylate
  • Glutamic Acid
  • Ibogaine
  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
  • Protein Glutamine gamma Glutamyltransferase 2
  • Transglutaminases
  • GTP-Binding Proteins
  • Glutathione
  • Pentazocine