Antioxidant properties and pharmacokinetic studies of new selective σ1 bifunctional ligands

We previously reported bifunctional sigma-1 (1) ligands endowed with antioxidant activity (1 and 2). In this work, pure enantiomers (R)-1 and (R)-2 along with the corresponding p-methoxy and p-fluoro derivatives were synthesized. 1 and 2 affinity, antioxidant properties, and preliminary pharmacokinetics studies were evaluated. Para derivatives, while maintaining strong 1 affinity, 1 selectivity compared to the parent compounds 1 and 2. Pharmacokinetic studies revealed that amides were more stable than corresponding esters under our experimental conditions. Antioxidant properties were exhibited by fluoro derivatives being able to increase total antioxidant capacity (TAC). Our results underline that p-substituents have an important role on 1 selectivity, TAC, chemical and enzymatic stabilities. In particular, our data suggest that new highly selective compounds could be promising tools to investigate the disorders in which 1 receptor dysfunction and oxidative stress are contemporarily involved.