Synthesis and quantitative structure-activity relationships of N-(1-benzylpiperidin-4-yl)phenylacetamides and related analogues as potent and selective sigma1 receptor ligands

Journal of Medicinal Chemistry
Y HuangRobert H Mach

Abstract

A series of N-(1-benzylpiperidin-4-yl)phenylacetamide derivatives was synthesized and evaluated for affinity at sigma1 and sigma2 receptors. Most of these compounds showed a high affinity for sigma1 receptors and a low to moderate affinity for sigma2 receptors. The unsubstituted compound N-(1-benzylpiperidin-4-yl)phenylacetamide, 1, displayed a high affinity and selectivity for sigma1 receptors (Ki values of 3.90 nM for sigma1 receptors and 240 nM for sigma2 receptors). The influence of substitutions on the phenylacetamide aromatic ring on binding at both the sigma1 and sigma2 receptor has been examined through Hansch-type quantitative structure-activity relationship (QSAR) studies. In general, all 3-substituted compounds, except for the OH group, had a higher affinity for both sigma1 and sigma2 receptors when compared with the corresponding 2- and 4-substituted analogues. The selectivity for sigma1 receptors displayed a trend of 3 > 2 approximately 4 for Cl, Br, F, NO2, and OMe substituted analogues. Halogen substitution on the aromatic ring generally increased the affinity for sigma2 receptors while maintaining a similar affinity for sigma1 receptors. Substitution with electron-donating groups, such as OH, OMe, or NH2, result...Continue Reading

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Citations

Dec 21, 2000·European Journal of Medicinal Chemistry·A MartinezA Badia
Mar 25, 2011·Future Medicinal Chemistry·Sanju NarayananChristopher R McCurdy
Feb 24, 2010·Journal of Pharmacological and Toxicological Methods·Sandhya Kortagere, Sean Ekins
Aug 8, 2013·Medicinal Research Reviews·Yun-Sheng HuangZongwen Wu
Aug 4, 2004·Cancer Research·Ebru AydarMustafa B A Djamgoz
Oct 14, 2020·European Journal of Medicinal Chemistry·Xiao-Yang XieYun-Sheng Huang
Dec 1, 2018·Journal of Chemical Information and Modeling·Youyi PengWilliam J Welsh
Jan 24, 2006·Journal of Chemical Information and Modeling·Yun-De XiaoJeffrey D Schmitt

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