Novel Potent and Selective σ Ligands: Evaluation of Their Agonist and Antagonist Properties

Novel enantiomers and diastereoisomers structurally related to sigma ligand (+)-MR200 were synthesized to improve sigma(1)/sigma(2) subtype selectivity. The selective sigma(1) ligand (-)-8 showed an antagonist profile determined by phenytoin differential modulation of binding affinity in vitro, confirmed in vivo by an increase of kappa opioid analgesia. The sigma(2) ligand (-)-9 displayed agonist properties in an in vitro isolated organ bath assay and antiproliferative effects on LNCaP and PC3 prostate cancer cell lines.