RO4583298

BACKGROUND AND PURPOSEClinical results of osanetant and talnetant (selective‐NK3antagonists) indicate that blocking the NK3receptor could be beneficial for the treatment of schizophrenia. The objective of this study was to characterize thein vitroandin vivoproperties of a novel dual NK1/NK3antagonist, RO4583298 (2‐phenyl‐N‐(pyridin‐3‐yl)‐N‐methylisobutyramide derivative).EXPERIMENTAL APPROACHRO4583298in vitropharmacology was investigated using radioligand binding ([3H]‐SP, [3H]‐osanetant, [3H]‐senktide), [3H]‐inositol‐phosphate accumulation Schild analysis (SP‐ or [MePhe7]‐NKB‐induced) and electrophysiological studies in guinea‐pig substantia nigra pars compacta (SNpc). Thein vivoactivity of RO4583298 was assessed using reversal of GR73632‐induced foot tapping in gerbils (GFT; NK1) and senktide‐induced tail whips in mice (MTW; NK3).KEY RESULTSRO4583298 has a high‐affinity for NK1(human and gerbil) and NK3(human, cynomolgus monkey, gerbil and guinea‐pig) receptors and behaves as a pseudo‐irreversible antagonist. Unusually it binds with high‐affinity to mouse and rat NK3, yet with a partial non‐competitive mode of antagonism. In guinea‐pig SNpc, RO4583298 inhibited the senktide‐induced potentiation of spontaneous activity of dopaminergic neurones with an apparent non‐competitive mechanism of action. RO4583298 (p.o.) robustly blocked the GFT response, and inhibited the MTW.CONCLUSIONS AND IMPLICATIONSRO4583298 is a high‐affinity, non‐competitive, long‐actingin vivoNK1/NK3antagonist; hence providing a usefulin vitroandin vivopharmacological tool to investigate the roles of NK1and NK3receptors in psychiatric disorders.