Progress in the development of neurokinin 3 modulators for the treatment of schizophrenia: molecule development and clinical progress.

The neuropeptide NK3 receptor is expressed almost exclusively within the mammalian nervous system and its localization is commensurate with a role in modulating central monoaminergic neurotransmission. Following on from our previous work we review the rationale for NK3 receptor antagonists as wide spectrum antipsychotics and the recent scientific and patent literature that has highlighted new chemical strategies to identify selective NK3 and dual activity NK1/3 receptor ligands for the putative treatment of schizophrenia. We discuss the emerging structural biology and its use in the design of molecules with increased structural diversity and predictable receptor pharmacology. Particular attention is paid to the progress in improving ligand drug-like properties. The status of imaging and the development of translational technologies in the neurokinin field are also discussed. Finally, we summarize the available clinical information on the compounds that have progressed into psychiatric patient populations and evaluate the potential therapeutic utility of NK3 receptor targeted ligands.