Studies on the Enantiomers of RC-33 as Neuroprotective Agents: Isolation, Configurational Assignment, and Preliminary Biological Profile

In this paper we addressed the role of chirality in the biological activity of RC-33, recently studied by us in its racemic form. An asymmetric synthesis procedure was firstly experimented, leading the desired enantioenriched RC-33 with an ee not good enough for supporting the in vitro investigation. An enantioselective HPLC procedure was then successfully carried out, yielding both RC-33 enantiomers in amount and optical purity suitable for the pharmacological study. The absolute configuration of pure enantiomers was easily assigned exploiting the asymmetric synthesis previously devised. As emerged by the preliminary in vitro biological investigation, (S)- and (R)-RC-33 possess a comparable affinity towards the σ1 receptor and a very a similar behaviour in the calcium influx assay, resulting equally effective as σ1 receptor agonist. Overall, results obtained so far suggest that the interaction with the biological target is non-stereoselective and lead us to hypothesize the lack of stereoselectivity in the biological activity of RC-33.