Identification of novel NK sub(1/NK) sub(3) dual antagonists for the potential treatment of schizophrenia

During the lead optimization of NK sub(1/NK) sub(3) receptor antagonists program, a focused exploration of molecules bearing a lactam moiety was performed. The aim of the investigation was to identify the optimal position of the carbonyl and hydroxy methyl group in the lactam moiety, in order to maximize the in vitro affinity and the level of insurmountable antagonism at both NK sub(1 and NK) sub(3) receptors. The synthesis and biological evaluation of these novel lactam derivatives, with potent and balanced NK sub(1/NK) sub(3) activity, were reported in this paper.