Synthesis and resolution of cis-(-)-methyl (1R,2S1S,2R)-2-(4-hydroxy-4-phenylpiperidin-1-yl)methyl-1-(4-methylphenyl)cyclopropanecarboxylate (-)-PPCC) new sigma receptor ligands with neuroprotective effect.
The enantiomers of cis-(-)-methyl (1R,2S1S,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.