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Papers of the Week

Papers: 26 Mar 2022 - 1 Apr 2022

Pharmacology/Drug Development

2022 Mar 30

Chem Biol Drug Des

Discovery of 3-(2-aminoethyl)-thiazolidine-2,4-diones as a Novel Chemotype of Sigma-1 Receptor Ligands.


Elkholy N, Abdelwaly A, Mohamed K, Amata E, Lombino J, Cosentino G, Intagliata S, Helal MA
Chem Biol Drug Des. 2022 Mar 30.
PMID: 35353926.


Sigma receptor is a transmembrane non-GPCR protein expressed mainly in the endoplasmic reticulum (ER) membrane associated with mitochondria. It is classified into two types; Sigma-1 (S1R) and Sigma-2 (S2R) based on their biological functions. S1R has been implicated in many neurological disorders such as anxiety, schizophrenia, and depression. Therefore, S1R ligands possess a variety of potential clinical applications with a great interest in the treatment of neuropathic pain. In this study, we report the discovery of a novel lead compound for S1R binding, based on the thiazolidine-2,4-dione nucleus. We have explored hydrophobic groups of different sizes on both sides of the five-membered ring scaffold guided by the crystal structure of S1R. Six compounds showed more than 50% displacement of the radioligand at 10 µM concentration with compound 6c resulting in 100% displacement and a K of 95.5 nM. Moreover, compounds 6c and 6e showed a significant selectivity over S2R. In addition, molecular docking predicted that all the compounds showed the critical salt bridge with Glu172 with variable degrees of π-stacking interaction with Tyr103. Upon optimization, this series of compounds could represent potential clinically useful S1R ligands for pain management.