title: Design, synthesis, and pharmacological evaluation of novel tetrahydroprotoberberine derivatives: selective inhibitors of dopamine D₁ receptor.
abstract: A series of new tetrahydroprotoberberine (THPB) derivatives were designed, synthesized, and tested for their binding affinity towards dopamine (D(1) and D(2)) and serotonin (5-HT(1A) and 5-HT(2A)) receptors. Many of the THPB compounds exhibited high binding affinity and activity at the dopamine D(1) receptor, as well as high selectivity for the D(1) receptor over the D(2), 5-HT(1A), and 5-HT(2A) receptors. Among these, compound 19c exhibited a promising D(1) receptor binding affinity (K(i)=2.53nM) and remarkable selectivity versus D(2)R (inhibition=81.87%), 5-HT(1A)R (inhibition=61.70%), and 5-HT(2A)R (inhibition=24.96%). Compared with l-(S)-stepholidine (l-SPD) (D(1)K(i)=6.23nM, D(2)K(i)=56.17nM), compound 19c showed better binding affinity for the D(1) receptor (2.5-fold higher) and excellent D(2)/D(1) selectivity. Functional assays found compounds 18j, 18k, and 19c are pure D(1) 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 D(1) receptor. These results are in accord with molecular docking studies.
authors: School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, People's Republic of China.
authors: Wangke
authors: W
authors: Qian
authors: Weijian
authors: W
authors: Lu
authors: Haifeng
authors: H
authors: Sun
authors: Zeng
authors: Z
authors: Li
authors: Liyuan
authors: L
authors: Zhu
authors: Rui
authors: R
authors: Zhao
authors: Lei
authors: L
authors: Zhang
authors: Shengbin
authors: S
authors: Zhou
authors: Yu
authors: Y
authors: Zhou
authors: Hualiang
authors: H
authors: Jiang
authors: Xuechu
authors: X
authors: Zhen
authors: Hong
authors: H
authors: Liu
mesh_terms: D001600:Berberine Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D001600:Berberine Alkaloids; D017447:Receptors, Dopamine D1; C014845:berbine