New bifunctional antioxidant/σ1 agonist ligands: preliminary chemico-physical and biological evaluation

We previously reported bifunctional sigma-1 (σ1) ligands endowed with antioxidant activity (1 and 2). In the present paper, pure enantiomers (R)-1 and (R)-2 along with the corresponding p-methoxy (6, 11), p-fluoro derivs. (7, 12) were synthesized. σ1 and σ2 affinities, antioxidant properties, and chemico-phys. profiles were evaluated. Para derivs., while maintaining strong σ1 affinity, displayed improved σ1 selectivity compared to the parent compds. 1 and 2. In vivo evaluation of compds. 1, 2, (R)-1, 7, and 12 showed σ1 agonist pharmacol. profile. Chemico-phys. studies revealed that amides 2, 11 and 12 were more stable than corresponding esters 1, 6 and 7 under our exptl. conditions. Antioxidant properties were exhibited by fluoro derivs. 7 and 12 being able to increase total antioxidant capacity (TAC). Our results underline that p-substituents have an important role on σ1 selectivity, TAC, chem. and enzymic stabilities. In particular, our data suggest that new very selective compds. 7 and 12 could be promising tools to investigate the disorders in which σ1 receptor dysfunction and oxidative stress are contemporarily involved