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

Sigma receptors are distributed in both central nervous system and peripheral tissues and are involved in a variety of physiological activities. Maurice at all. showed that activation of "1 prevents neuronal death caused by excitotoxicity. 1 It has also been shown that hyperstimulation of glutamate receptors provoke a neuronal loss. 2 Previous study of Campisi et all. demostrate that glutamate expoisure of differentiated astricytes provokes an increase of [Ca 2+ ], a decrease of ATP concentration and ROS production, mithocondrial impairment and activation of a variety of calcium- dependent proteins. 3 Campisi et all. also showed how the recovery of cellular redox state given by antioxidants, is closely linked to a contemporary and dose-dependent reduction of transglutaminase-2 (TG2) up-regulation induced by glutamate. 4 We have previous reported the synthesis and biological profiles of " selective ligand (±)-PPCC and we demonstrated that this compound was able to modulate TG2 expression in primary rat astroglial cell cultures. 5,6 We here report the synthesis of pure diastereoisomers and their capability of restoring the astroglial oxidative status modified by glutamate, counteracting also TG2 overexpression. 7 To assess protective effects of sigma ligands on DNA damages induced by glutamate, we are investigating and reporting some data of p21 expression.