Table 1. Activity of 1–15 on TLX in the VP16/TLX Setting^a.

ID		R1	R2	R3	X–Y	R4	IC50 (fold TLX repression)
2	xanthine	H	H	H	N=C	H	inactive at 100 μM
1	1-methylxanthine	Me	H	H	N=C	H	9 ± 3 μM (2.3 ± 0.3)
3	3-methylxanthine	H	Me	H	N=C	H	inactive at 100 μM
4	7-methylxanthine	H	H	Me	N=C	H	inactive at 100 μM
5	theophylline	Me	Me	H	N=C	H	10 ± 2 μM (2.6 ± 0.1)
6	paraxanthine	Me	H	Me	N=C	H	11 ± 2 μM (2.4 ± 0.1)
7	theobromine	H	Me	Me	N=C	H	inactive at 100 μM
8	caffeine	Me	Me	Me	N=C	H	9 ± 2 μM (2.3 ± 0.1)
9	uric acid	H	H	H	HN–C	=O	inactive at 100 μM
10	1-methyluric acid	Me	H	H	HN–C	=O	25 ± 3 μM (1.7 ± 0.1)
11	1,7-dimethyluric acid	Me	H	Me	HN–C	=O	44 ± 4 μM (3.0 ± 0.2)
12	1,3,7-trimethyluric acid	Me	Me	Me	HN–C	=O	24 ± 3 μM (2.7 ± 0.2)
13	8-bromotheophylline	Me	Me	H	N=C	Br	6 ± 3 μM (1.6 ± 0.1)
14	8-chlorotheophylline	Me	Me	H	N=C	Cl	17 ± 3 μM (2.1 ± 0.2)
15	8-phenyltheophylline	Me	Me	H	N=C	Ph	0.5 ± 0.3 μM (2.4 ± 0.2)

^aCompounds were tested to a maximum concentration of 100 μM. Fold repression refers to the maximum fold increase in the reporter activity (compared to 0.1% DMSO) resulting from the inhibition of TLX. Control experiments on Gal4-VP16 in the absence of Gal4-TLX have excluded non-specific effects and confirmed TLX-mediated activity for all active compounds. All data are mean ± SEM, n ≥ 3.