The 5-phenyl substituent indeed tolerated more modifications (18-28, Table ). Both a methyl group (18) and a chlorine atom (19) in 2-position caused a slight improvement in potency but also a loss in efficacy. Modification of the 3-position with a methyl (20) or a chloro substituent (21) was tolerated, too, with preference for the chlorine atom. In para-position, the same substituents disrupted inverse Nurr1 agonism (22, 23). This SAR again markedly differed from RXR where modifications in 2-position had no effect while (lipophilic) derivatization in the 3-and 4-positions was highly favored . Substituents in 2-position hence emerged as an avenue to obtain selectivity for Nurr1 over RXR while the 3-position appeared to hold potential to improve potency. We explored this region further with alternative substituents but neither the 2-and 3-methoxy analogues (24, 25), nor the 3-trifluoromethyl (26) derivative provided enhanced inverse Nurr1 agonism and also the 2,3-dichloro derivative 27 was less active than the mono-chloro analogues 19 and 21. Based on the hypothesis that the higher potency of the ortho-substituted derivatives 18 and 19 might arise from a locked dihedral conformation, we evaluated the 2,6-dimethyl derivative 28 which would promote this effect, but 28 failed to suppress Nurr1 activity and rather acted as weak Nurr1 agonist. The selectivity index (SI) was calculated by dividing the EC50 for RXRα activation by the IC50 for Nurr1 inhibition. c Activity data on RXR have been reported previously . d Activity data on Nurr1 have been reported previously . e Too toxic for characterization at higher concentrations.