Synthesis and NK(1)/NK(2) binding activities of a series of diacyl-substituted 2-arylpiperazines.

The synthesis and binding affinity for hNK(1) and hNK(2) receptors of a series of diacyl substituted 2-aryl piperazines are described. SAR evaluation led to the racemic derivative 11g as an apparent dual inhibitor. Chiral chromatographic separation of 11g led to the observation that NK(1) activity was shown by one enantiomer (13a) and NK(2) activity was shown by the other enantiomer (13b). X-ray crystallographic analysis of the crystalline di-BOC derivative of the NK(2) active piperazine (15) showed that the 2R configuration was associated with NK(2) activity. Further derivatization indicated that dual NK(1)/NK(2) activity could be built into the 2R series.