IRX4204 (AGN194204) is a potent, specific and brain penetrable pan-RXR agonist, fully activates all three RXRs (α, β and γ) at 1 nM, activates nuclear receptor Nurr1 downstream signaling.
IRX4204 is thousand times more potent for RXR than retinoic acid receptors (RARα, β and γ), does not activate the RXR heterodimers of farnesoid X receptor (FXR), liver X receptors (LXR) α and β, or peroxisome proliferator-activated receptor PPARγ.
IRX4204 potently activated reporter gene transcription in a RXR dependent manner (EC50 <1 nM), IRX4204 is an effective activator of RXR/Nurr1 heterodimers.
IRX4204 (1 nM) significantly increased the expression of dopamine transporter (DAT) and dopa-decarboxylase (DDC) in VMB neurons, which could be abolished by RXR antagonist HX531.
IRX4204 is bioactive in the brains following oral administration and activates Nurr1 downstream genes in the substantia nigra (SN).
IRX4204 (10mg/kg/day, oral) improves motor asymmetry and dopamine neuron loss in a rat model of PD.