Using the VP16/TLX reporter gene assay, we then screened a drug fragment library comprising 480 small organic molecules (MW range 80-300 g/mol) for TLX modulatory activity and discovered 1-methylxanthine (1) as TLX modulator that diminished TLX-mediated transcriptional repression with an IC50 value of 9±3 µM (Table ) suggesting inverse agonism. Intrigued by this activity, we studied the structurally related xanthines 2-8 for TLX modulation. 2-4 and 7 were inactive on TLX whereas theophylline (5), paraxanthine (6) and caffeine (8, Figure ) counteracted TLX-dependent transcriptional repression as well. Control experiments in absence of the Gal4-TLX hybrid receptor revealed no unspecific effects of the xanthines confirming their TLX-mediated activity (Figure ).