Design, synthesis, and pharmacological evaluation of novel tetrahydroprotoberberine derivatives: Selective inhibitors of dopamine D 1 receptor

Article abstract of DOI:10.1016/j.bmc.2012.05.057

A series of new tetrahydroprotoberberine (THPB) derivatives were designed, synthesized, and tested for their binding affinity towards dopamine (D ₁ and D₂) and serotonin (5-HT_1A and 5-HT _2A) receptors. Many of the THPB compounds exhibited high binding affinity and activity at the dopamine D₁ receptor, as well as high selectivity for the D₁ receptor over the D₂, 5-HT _1A, and 5-HT_2A receptors. Among these, compound 19c exhibited a promising D₁ receptor binding affinity (K_i = 2.53 nM) and remarkable selectivity versus D₂R (inhibition = 81.87%), 5-HT_1AR (inhibition = 61.70%), and 5-HT_2AR (inhibition = 24.96%). Compared with l-(S)-stepholidine (l-SPD) (D₁ K_i = 6.23 nM, D₂ K_i = 56.17 nM), compound 19c showed better binding affinity for the D₁ receptor (2.5-fold higher) and excellent D₂/D₁ selectivity. Functional assays found compounds 18j, 18k, and 19c are pure D₁ receptor antagonists. These results indicate that removing the C10 hydroxy group and introducing a methoxy group at C11 of the pharmacophore of l-SPD can reverse the function of THPB compounds at the D₁ receptor. These results are in accord with molecular docking studies.