Synthesis and Resolution of cis -(±)-Methyl (1 R ,2 S /1 S ,2 R )-2-[(4-Hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl)cyclopropanecarboxylate [(±)-PPCC)]: New σ Receptor Ligands with Neuroprotective Effect

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 σ ligand, were synthesized. The (+)- and (−)-enantiomers bind predominantly to σ1 receptors and have a reduced σ2 affinity. Both individually restore the astroglial oxidative status modified by glutamate, counteracting also transglutaminase-2 overexpression. They exhibited in vivo anti-opioid effects on κ opioid (KOP) receptor-mediated analgesia. Our findings demonstrate that the enantiomers display mainly σ1 agonist activity and that they have neuroprotective effects.

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