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Author Donnier-Marechal, Marion ♦ Carato, Pascal ♦ Larchanché, Paul-Emmanuel ♦ Ravez, Séverine ♦ Boulahjar, Rajâa ♦ Barczyk, Amelie ♦ Oxombre, Bénédicte ♦ Vermersch, Patrick ♦ Melnyk, Patricia
Source Hyper Articles en Ligne (HAL)
Content type Text
Publisher Elsevier
File Format PDF
Language English
Subject Keyword Benzamide ♦ Sigma protein ♦ CNS ♦ chim ♦ Chemical Sciences/Medicinal Chemistry
Abstract A series of novel benzamide-derived compounds was designed, synthesized and pharmacologically evaluated. Among all 37 synthesized compounds, two series were developed with the modulation of the nature, the position of atoms or groups on the benzamide scaffold, but also the nature of the amine group separated from the benzamide with 2, 3 or 4 methylene groups. In vitro competition binding assays against sigma proteins (sigma-1 S1R and sigma-2 S2R) revealed that most of them conferred S2R/S1R selectivity toward without cytotoxic effects on SY5Y cells, especially with the first series with compounds 7a-z. Some selected compounds were also evaluated for their agonist and antagonist activities on a panel of 40 receptors. Results showed the importance of the nature and the position with halogeno atom on the benzamide scaffold, the length chain but also the contribution of the hydrophobic part on the amine group. Among them, compounds 7i, w, y with Cl, CN or NO2 groups at the 4-position of the benzamide scaffold showed excellent affinity for S1R (Ki = 1.2–3.6 nM), selectivity for S2R (Ki up to 1400 nM) and high selectivity index (IC50(SY5Y)/Ki(S1R) ratio from 28 000 to 83 000). Futhermore, these compounds presented an excellent safety profile over 40 other receptors. These derivatives will be selected for further biological investigations.
ISSN 02235234
Educational Use Research
Learning Resource Type Article
Publisher Date 2017-01-01
e-ISSN 17683254
Journal European Journal of Medicinal Chemistry
Volume Number 138
Page Count 15
Starting Page 964
Ending Page 978