Issue 1, 2015

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

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?

Supplementary files

Article information

Article type
Concise Article
Submitted
13 Aug 2014
Accepted
17 Sep 2014
First published
18 Sep 2014

Med. Chem. Commun., 2015,6, 138-146

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

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Spotlight

Advertisements