Jump to main content
Jump to site search
Access to RSC content Close the message box

Continue to access RSC content when you are not at your institution. Follow our step-by-step guide.


Issue 1, 2015
Previous Article Next Article

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

Author affiliations

Abstract

In our recent research racemic RC-33 was identified as a potent and highly promising σ1 receptor agonist, showing excellent σ1 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 σ1 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 σ1 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.

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

Back to tab navigation

Supplementary files

Article information


Submitted
13 Aug 2014
Accepted
17 Sep 2014
First published
18 Sep 2014

Med. Chem. Commun., 2015,6, 138-146
Article type
Concise Article

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

D. Rossi, A. Marra, M. Rui, E. Laurini, M. Fermeglia, S. Pricl, D. Schepmann, B. Wuensch, M. Peviani, D. Curti and S. Collina, Med. Chem. Commun., 2015, 6, 138
DOI: 10.1039/C4MD00349G

Search articles by author

Spotlight

Advertisements