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Issue 13, 2018
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Discovery of N-cyclobutylaminoethoxyisoxazole derivatives as novel sigma-1 receptor ligands with neurite outgrowth efficacy in cells

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Abstract

Herein we reported a series of 14 novel derivatives based on the N-cyclobutylaminoethoxyisoxazole scaffold. In vitro binding studies of these compounds demonstrated their low nanomolar to subnanomolar potencies as σ1 receptor ligands, with moderate to excellent selectivity over the σ2 receptor as represented by compounds 17–30. The majority of the derivatives scored high (>4.7) in the CNS MPO appraisal system, indicating their high likelihood in penetrating the blood–brain barrier. A number of these compounds exhibited significant neurite outgrowth efficacy in N1E-115 neuronal cells and displayed excellent selectivity for σ1 receptors over the selected endogenous neurotransmitter transporters, such as DAT, NET and SERT. Among the mini-series, compound 28 (Ki σ1 = 0.2 nM, Ki σ2 = 198 nM, CNS MPO score = 5.4) emerged as a promising selective σ1 receptor ligand that warrants its further evaluation as a potential therapeutic for neurodegenerative diseases.

Graphical abstract: Discovery of N-cyclobutylaminoethoxyisoxazole derivatives as novel sigma-1 receptor ligands with neurite outgrowth efficacy in cells

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Supplementary files

Article information


Submitted
04 Jan 2018
Accepted
06 Feb 2018
First published
14 Feb 2018

This article is Open Access

RSC Adv., 2018,8, 7080-7088
Article type
Paper

Discovery of N-cyclobutylaminoethoxyisoxazole derivatives as novel sigma-1 receptor ligands with neurite outgrowth efficacy in cells

H. Sun, Y. Wang, W. Shi, F. Yang, J. Tang, T. Pang and L. Yu, RSC Adv., 2018, 8, 7080
DOI: 10.1039/C8RA00072G

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