Synthesis, pharmacological evaluation and \u3c31 receptor interaction analysis of hydroxyethyl substituted piperazines

Starting from (S)- or (R)-aspartate, three synthetic strategies were explored to prepare hydroxyethyl substituted piperazines with different substituents at the N-atoms. \u3c3 receptor affinity was recorded using receptor material from both animal and human origin. \u3c31 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 \u3c31 receptors (Ki = 6.8 nM). The potent \u3c31 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 \u3c31 receptor was analyzed in detail using the 3D homology model of the \u3c31 receptor. The calculated free binding energies of all hydroxyethylpiperazines nicely correlate with their recorded affinities toward the human \u3c31 receptor