title: Synthesis, pharmacological evaluation, and σ1 receptor interaction analysis of hydroxyethyl substituted piperazines.
abstract: Starting from (S)- or (R)-aspartate, three synthetic strategies were explored to prepare hydroxyethyl substituted piperazines with different substituents at the N-atoms. σ receptor affinity was recorded using receptor material from both animal and human origin. σ1 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 σ1 receptors (Ki = 6.8 nM). The potent σ1 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 σ1 receptor was analyzed in detail using the 3D homology model of the σ1 receptor. The calculated free binding energies of all hydroxyethylpiperazines nicely correlate with their recorded affinities toward the human σ1 receptor.
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster , Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Weber
authors.forename: Stefanie
authors.initials: S
authors.lastname: Brune
authors.forename: Katharina
authors.initials: K
authors.lastname: Korpis
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Bednarski
authors.forename: Erik
authors.initials: E
authors.lastname: Laurini
authors.forename: Valentina
authors.initials: V
authors.lastname: Dal Col
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pricl
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000378:metabolism; D002855:Chromatography, Thin Layer; D006168:Guinea Pigs; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011485:Protein Binding; D017480:Receptors, sigma / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C000589309:2-(4-(cyclohexylmethyl)-1-(naphthalene-2-ylmethyl)piperazin-2-yl)ethanol; D000970:Antineoplastic Agents; D010879:Piperazines; D017480:Receptors, sigma