A step forward in the sigma enigma: a role for chirality in the sigma1 receptor–ligand interaction?

In our recent research racemic RC-33 was identified as a potent and highly promising sigma(1) receptor agonist, showing excellent sigma(1) receptor affinity and promoting NGF-induced neurite outgrowth in PC12 cells at very low concentrations. Surprisingly, both its interaction with the biological target and its effect on neurite sprouting proved to be non-stereoselective. Starting from the observation that a hydrogen bond center in the scaffold of a sigma(1) ligand is an important pharmacophoric element for receptor/ligand interaction, we hypothesized that the absence of such pharmacophoric feature in the structure of RC-33 could be also responsible for the lack of enantioselectivity in its interaction with the target receptor. To verify our hypothesis, in this paper we evaluated - both in silico and in vitro - the ability of a series of enantiomeric arylalkylaminoalcohols and arylpyrrolidinols 1-5 to interact with the receptor. All these compounds are structurally related to RC-33 and are characterized by the presence of an -OH group as the additional pharmacophore feature. Interestingly, the results of our study show that the sigma(1) receptor exhibits enantiopreference toward compounds characterized by (S)-configuration at the stereogenic center bearing the aromatic moiety only when the alcoholic group is also present at that chiral center, thus supporting our original hypothesis.