Effects of tetrahydroprotoberberines on dopamine receptor subtypes in brain.

The effects of 12 tetrahydroprotoberberines (THPBs) on D1 and D2 receptors labelled with [3H]DA, [3H]Sch-23390 and [3H]spiperone were evaluated. Their effects on the activity of adenylate cyclase stimulated with DA 40 mumols/L were also assessed. All of the l-THPBs tested behaved as DA receptor antagonists with preferential affinity toward the D1 receptors. Among them, l-stepholidine (l-SPD), a THPB analog with 2 hydroxy groups at the C2 and C10 positions, was the most potent. Its affinity toward D1 receptors was 4-7 times higher than that toward D2 receptors. The results suggest that the hydroxy groups in l-THPBs are very important factors in determining the affinity to DA receptors. Moreover, d-tetrahydropalmatine (d-THP), a dextro-THPB analog, displayed no affinity for the D2 receptor subtype, while its optical isomer, l-THP, was a DA receptor antagonist. This indicates that the levo-optical configuration is necessary for the affinity of THPBs to DA receptors. In addition, l-SPD was 18 times more potent than haloperidol with respect to binding to D1 receptors, but 14 times weaker for D2 receptors. Thus, it is expected that the clinical effects of l-SPD can be distinguished from that of haloperidol.