Synthesis, Pharmacological Evaluation, and 蟽1 Receptor Interaction Analysis of Hydroxyethyl Substituted Piperazines

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• 作者：Frauke Weber ; Stefanie Brune ; Katharina Korpis ; Patrick J. Bednarski ; Erik Laurini ; Valentina Dal Col ; Sabrina Pricl ; Dirk Schepmann ; Bernhard W眉nsch
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：April 10, 2014
• 年：2014
• 卷：57
• 期：7
• 页码：2884-2894
• 全文大小：429K
• 年卷期：v.57,no.7(April 10, 2014)
• ISSN：1520-4804

文摘

Starting from (S)- or (R)-aspartate, three synthetic strategies were explored to prepare hydroxyethyl substituted piperazines with different substituents at the N-atoms. 蟽 receptor affinity was recorded using receptor material from both animal and human origin. 蟽₁ affinities determined with guinea pig brain and human RPMI 8226 tumor cell lines differed slightly but showed the same tendency. (S)-2-[4-(Cyclohexylmethyl)-1-(naphthalene-2-ylmethyl)piperazin-2-yl]ethanol (7c) revealed the highest affinity at human 蟽₁ receptors (K_i = 6.8 nM). The potent 蟽₁ receptor ligand 7c was able to inhibit selectively the growth of three human tumor cell lines with IC₅₀ values in the low micromolar range. The reduced growth of the RPMI-8226 cell line was caused by apoptosis. The interaction of 7c with the 蟽₁ receptor was analyzed in detail using the 3D homology model of the 蟽₁ receptor. The calculated free binding energies of all hydroxyethylpiperazines nicely correlate with their recorded affinities toward the human 蟽₁ receptor.