Identification of novel NK₁/NK₃ dual antagonists for the potential treatment of schizophrenia

During the lead optimization of NK₁/NK₃ 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 NK₁ and NK₃ receptors. The synthesis and biological evaluation of these novel lactam derivatives, with potent and balanced NK₁/NK₃ activity, were reported in this paper.