Development of novel phenoxyalkylpiperidines as high-affinity Sigma-1 (σ1) receptor ligands with potent anti-amnesic effect - Archive ouverte HAL Access content directly
Journal Articles European Journal of Medicinal Chemistry Year : 2022

Development of novel phenoxyalkylpiperidines as high-affinity Sigma-1 (σ1) receptor ligands with potent anti-amnesic effect

(1) , (2) , (1) , (1) , (1) , (1) , (1) , (3) , (3) , (1) , (1)
1
2
3

Abstract

The sigma-1 (σ1) receptor plays a significant role in many normal physiological functions and pathological disease states, and as such represents an attractive therapeutic target for both agonists and antagonists. Here, we describe a novel series of phenoxyalkylpiperidines based on the lead compound 1-[ω-(4-chlorophenoxy)ethyl]-4-methylpiperidine (1a) in which the degree of methylation at the carbon atoms alpha to the piperidine nitrogen was systematically varied. The affinity at σ1 and σ2 receptors and at Δ8-Δ7 sterol isomerase (SI) ranged from subnanomolar to micromolar Ki values. While the highest-affinity was displayed at the σ1, the increase of the degree of methylation in the piperidine ring progressively decreased the affinity. The subnanomolar affinity 1a and 1-[ω-(4-methoxyphenoxy)ethyl]-4-methylpiperidine (1b) displayed potent anti-amnesic effects associated with σ1 receptor agonism, in two memory tests. Automated receptor-small-molecule ligand docking provided a molecular structure-based rationale for the agonistic effects of 1a and 1b. Overall, the class of the phenoxyalkylpiperidines holds potential for the development of high affinity σ1 receptor agonists, and compound 1a, that appears as the best in class (exceeding by far the activity of the reference compound PRE-084) deserves further investigation.
Not file

Dates and versions

inserm-03845632 , version 1 (09-11-2022)

Identifiers

Cite

Francesca Abatematteo, Philip Mosier, Mauro Niso, Leonardo Brunetti, Francesco Berardi, et al.. Development of novel phenoxyalkylpiperidines as high-affinity Sigma-1 (σ1) receptor ligands with potent anti-amnesic effect. European Journal of Medicinal Chemistry, 2022, 228, pp.114038. ⟨10.1016/j.ejmech.2021.114038⟩. ⟨inserm-03845632⟩
0 View
0 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More