Chemical, pharmacological, and in vitro metabolic stability studies on enantiomerically pure RC-33 compounds, promising neuroprotective agents acting as sigma1 receptor agonists.

In our recent researches racemic RC-33 was identified as a potent and metabolically stable σ1 receptor agonist. Herein we describe the isolation of RC-33 pure enantiomers by enantioselective chromatography, their absolute configuration assignment, and in vitro biological study, in order to address the role of chirality in their biological activity and metabolic processes. The binding of enantiopure RC-33 towards σ1 receptor was also investigated in silico by means of molecular dynamics simulations. Both RC-33 enantiomers showed a comparable affinity for the σ1 receptor and appeared to be almost equally effective as σ1 receptor agonists. On the contrary, the (R) configured enantiomer showed higher in vitro hepatic metabolic stability in the presence of NADPH with respect to the (S) configured one. Overall, results presented in this contribution led us to select (R)-RC-33 as the optimal candidate for further in vivo studies in animal model of amyotrophic lateral sclerosis.