Systematic structural modification of the caffeine chemotype favourably led to a dramatic increase in potency on TLX, exemplified by 29 (IC50 160 nM, 2.9-fold TLX repression), 33 (40 nM, 4.0-fold) and 34 (9 nM, 3.0-fold). In addition, we discovered the recently approved drug istradefylline (30) as a potent TLX modulator (IC50 40 nM, 2.6-fold TLX repression). This activity might prove as important feature of the drug's pharmacological profile since TLX, characterized as essential regulator of NSC homeostasis and neurogenesis , could involve in the pathology and treatment of PD. Furthermore, TLX is a crucial factor for spatial learning and a recent rodent AD model has demonstrated improvements in memory and spatial learning in istradefylline treated animals further suggesting a potential involvement of TLX in the drug's pharmacology.