GSK256471

GSK256471 is a non-peptide tachykinin NK3 receptor antagonist with a pK_i of 8.9 for the human recombinant NK3 receptor and 8.4 for the guinea pig native receptor. GSK256471 exhibits >100-fold selectivity for NK1 (pK_i = 5.2) and NK2 (pK_i = 7.3) receptors. GSK256471 noncompetitively inhibits neurokinin B (NKB) (HY-P0242)-induced inositol phosphate accumulation, and this inhibition is irreversible. GSK256471 inhibits wet dog shaking behavior and suppresses dopamine release. GSK256471 could be used to study schizophrenia^[1][2]. In Vitro:GSK256471 inhibits the intracellular calcium release induced by NKB with a pK_i of 8.9^[1].
GSK256471 (0.01-1 μM) causes the NKB concentration-response curve to shift to the right and significantly reduces the maximum response (Emax), indicating the non-competitive antagonistic property in U2OS cells^[2].
GSK256471 (0.1-1 μM) completely abolished the neuronal discharge caused by NKB in U2OS cells^[2].
In Vivo:GSK256471 (1-10 mg/kg, i.v., p.o. and i.p., single dose) has moderate brain penetration, but its high affinity compensates for the low exposure dose in rats and gerbils^[1][2].
GSK256471 (1 ng/kg-100 mg/kg, i.p., single dose) achieves effective receptor occupation at low brain concentrations with an EC₅₀ of 8 ng/g^[2].
GSK256471 (3-30 mg/kg, i.p., single dose) effectively blocks the function of the central NK3 receptor and inhibits the "wet dog shake" behavior in guinea pigs^[2].
GSK256471 (1-30 mg/kg, i.p., single dose) regulates the excessive activity of the mesolimbic dopamine system in the brain of guinea pigs, suggesting its potential as an antipsychotic agent^[2].