Issue 9, 2023

Discovery and computational studies of piperidine/piperazine-based compounds endowed with sigma receptor affinity

Abstract

Herein, we describe our efforts to identify sigma receptor 1 (S1R) ligands through a screening campaign on our in-house collection of piperidine/piperazine-based compounds. Our investigations led to the discovery of the potent compound 2-[4-(benzyl)-1-piperidin-1-yl]-1-4-(4-phenylpiperazin-1-yl)ethanone (1) with high affinity toward S1R (Ki value of 3.2 nM) that was comparable to reference compound haloperidol (Ki value of 2.5 nM). Functional assay revealed that compound 1 acted as S1R agonist. To decipher the binding mode of this promising S1R ligand as a starting point for further structure-based optimization, we analysed the docking pose by using a S1R-structure derived from cocrystal structures of potent ligands in complex with target protein. The computational study was enriched with molecular dynamic simulations that revealed the crucial amino acid residues that interacted with the most interesting compound 1.

Graphical abstract: Discovery and computational studies of piperidine/piperazine-based compounds endowed with sigma receptor affinity

Supplementary files

Article information

Article type
Research Article
Submitted
23 Jun 2023
Accepted
26 Jul 2023
First published
26 Jul 2023
This article is Open Access
Creative Commons BY license

RSC Med. Chem., 2023,14, 1734-1742

Discovery and computational studies of piperidine/piperazine-based compounds endowed with sigma receptor affinity

L. De Luca, L. Lombardo, S. Mirabile, A. Marrazzo, M. Dichiara, G. Cosentino, E. Amata and R. Gitto, RSC Med. Chem., 2023, 14, 1734 DOI: 10.1039/D3MD00291H

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