Therapeutic utility of NK3 receptor antagonists for the treatment of schizophrenia.

The dopaminergic and glutamatergic hypotheses dominate current drug discovery strategies. The dopamine hypothesis states that hyperactivity of the mesolimbic dopaminergic pathway is associated with positive symptoms of the disease, whereas hypoactivity of the mesocortical dopaminergic pathway is associated with the negative and cognitive symptoms. Increasing evidence has also suggested that hypoactivity in the corticolimbic glutamatergic system may contribute to the complex interplay between dysfunctional aspects of these neurotransmitter systems, which could account for much of the symptomatology observed in schizophrenia. Current antipsychotic drugs display moderate efficacy in treating the positive symptoms and limited efficacy against the negative, cognitive, or co-morbidity symptoms of the disease. They are also associated with significant side effects such as extrapyramidal side effects and metabolic disturbances. Thus pharmacologies that are able to more selectively modulate the underlying neuronal substrates of schizophrenia may have utility as efficacious and wide spectrum antipsychotic therapies with potentially improved side effect liabilities. The neuropeptide neuromodulator/neurotransmitter class and their associated receptors have been suggested to be one such family class. One such target which has shown particular promise, and thus has gained much pharmaceutical research interest, is the neurokinin receptor family and particularly the NK(3) receptor. The NK(3) receptor is expressed almost exclusively within the mammalian nervous system and its localisation is commensurate with a role in modulating central monoaminergic neurotransmission. Here we will provide an introduction to both the neurokinin ligands and receptors and review current preclinical understanding of their putative biological roles and, in particular, their modulatory role in the circuitry pertinent to schizophrenia. A brief review of the available chemical strategies employed to produce selective tools and drug development candidates will also be undertaken. Finally we will summarize the available clinical information on those compounds which have progressed into patient populations and evaluate their potential therapeutic utility, and the future of the NK(3) receptor target.