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

Autor: Abatematteo FS; Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari, ALDO MORO, Via Orabona, 4, I-70125, Bari, Italy., Mosier PD; Department of Biopharmaceutical Sciences, School of Pharmacy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA., Niso M; Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari, ALDO MORO, Via Orabona, 4, I-70125, Bari, Italy., Brunetti L; Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari, ALDO MORO, Via Orabona, 4, I-70125, Bari, Italy., Berardi F; Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari, ALDO MORO, Via Orabona, 4, I-70125, Bari, Italy., Loiodice F; Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari, ALDO MORO, Via Orabona, 4, I-70125, Bari, Italy., Contino M; Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari, ALDO MORO, Via Orabona, 4, I-70125, Bari, Italy., Delprat B; MMDN, University of Montpellier, EPHE, INSERM, Montpellier, France., Maurice T; MMDN, University of Montpellier, EPHE, INSERM, Montpellier, France., Laghezza A; Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari, ALDO MORO, Via Orabona, 4, I-70125, Bari, Italy. Electronic address: antonio.laghezza@uniba.it., Abate C; Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari, ALDO MORO, Via Orabona, 4, I-70125, Bari, Italy. Electronic address: carmen.abate@uniba.it.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2022 Jan 15; Vol. 228, pp. 114038. Date of Electronic Publication: 2021 Dec 03.
DOI: 10.1016/j.ejmech.2021.114038
Abstrakt: The sigma-1 (σ 1 ) 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 σ 1 and σ 2 receptors and at Δ 8 -Δ 7 sterol isomerase (SI) ranged from subnanomolar to micromolar K i values. While the highest-affinity was displayed at the σ 1 , 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 σ 1 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 σ 1 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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