The NK1R was the first neuropeptide receptor for which a potent, highly selective non-peptide antagonist was developed (Snider et al., 1991). Subsequent drug development efforts targeting this receptor were in part complicated by the fact that it displays considerable divergence between species, and many compounds that have high affinity for the human NK1R do not effectively bind the rat NK1R (Jensen et al., 1994; Leffler et al., 2009). NK1R antagonists have been explored for the treatment of inflammatory conditions, depression, and chemotherapy-induced nausea [for review, see e.g. (Quartara et al., 2009)]. With one exception, the treatment of chemotherapy-induced nausea, efforts targeting NK1R have not resulted in therapeutics approved for clinical use. Although previous attempts to develop NK1R antagonists for depression were unsuccessful, recent studies have provided renewed support for their antidepressant potential, but indicated that near-complete central receptor occupancy might be required to achieve this effect (Ratti et al., 2011; Zamuner et al., 2012).
