Novel tetrahydroisoquinoline (THI) analogs were designed, synthesized, and their antiglioma activity was evaluated. The results showed that 6,8-dimethoxy-1-(20 methoxybiphenyl-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (25) demonstrated improved potency, and selectivity on C6 rat glioma vs cultured rat astrocytes (EC50 0.63 lM vs. 10.85 lM) compared to our recent lead molecule EDL-155 (EC50 1.5 lM vs. 27.4 lM). The isomers of 25 were isolated using a semi-preparative high-performance liquid chromatography (HPLC) method, and their in vitro biological evaluation revealed that (?) 25 was the most active, and it was nearly 21 fold more potent than (-) 25, suggesting the antiglioma profile is influenced by stereochemical factors.