Faculty Collaboration Database

Development of novel phenoxyalkylpiperidines as high-affinity Sigma-1 (σ₁) receptor ligands with potent anti-amnesic effect. Eur J Med Chem 2022 Jan 15;228:114038

Date

12/14/2021

Pubmed ID

34902734

DOI

10.1016/j.ejmech.2021.114038

Scopus ID

2-s2.0-85120886359 (requires institutional sign-in at Scopus site)   2 Citations

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 K_i 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.

Author List

Abatematteo FS, Mosier PD, Niso M, Brunetti L, Berardi F, Loiodice F, Contino M, Delprat B, Maurice T, Laghezza A, Abate C

Author

Philip Mosier PhD Assistant Professor in the School of Pharmacy Administration department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amnesia
Animals
Cell Survival
Dose-Response Relationship, Drug
Guinea Pigs
Humans
Ligands
Male
Mice
Models, Molecular
Molecular Structure
Piperidines
Rats
Rats, Wistar
Receptors, sigma
Structure-Activity Relationship
Tumor Cells, Cultured