Chemical synthesis, microbial transformation and biological evaluation of tetrahydroprotoberberines as dopamine D1/D2 receptor ligands. Issue 10 (15th May 2019)

• Record Type: Journal Article
• Authors: Ge, Haixia; Zhang, Yan; Yang, Zhuo; Qiang, Kun; Chen, Chao; Sun, Laiyu; Chen, Ming; Zhang, Jian
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 10(2019)
• Page Start: 2100
• Page End: 2111
• Publication Date: 2019-05-15
• Subjects: Tetrahydroprotoberberines -- Dopamine D1/D2 receptors -- Antagonistic activities -- Microbial transformation -- Molecular simulations; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.04.014
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: THPBs derivatives were prepared by chemical synthesis or microbial transformation. The functional activity of compounds on D1/D2 receptors were tested. 5 Compounds displayed selective antagonistic activity on D2 receptor. Abstract: Dopamine D1/D2 receptors are important targets for drug discovery in the treatment of central nervous system diseases. To discover new and potential D1/D2 ligands, 17 derivatives of tetrahydroprotoberberine (THPB) with various substituents were prepared by chemical synthesis or microbial transformation using Streptomyces griseus ATCC 13273. Their functional activities on D1 and D2 receptors were determined by cAMP assay and calcium flux assay. Seven compounds showed high activity on D1/D2 receptor with low IC50 values less than 1 µM. Especially, top compound5 showed strong antagonistic activity on both D1 and D2 receptor with an IC50 of 0.391 and 0.0757 µM, respectively. Five compounds displayed selective antagonistic activity on D1 and D2 receptor. The SAR studies revealed that (1) the hydroxyl group at C-9 position plays an important role in keeping a good activity and small or fewer substituents on ring D of THPBs may also stimulate their effects, (2) the absence of substituents at C-9 position tends to be more selective for D2 receptor, and (3) hydroxyl substitution at C-2 position and the substitution at C-9 position may facilitate the conversion of D1 receptor from antagonist to agonist. Molecular docking simulations found that Asp 103/Asp 114, Ser 107/Cys 118, and Trp 285/ Trp 386 of D1/ D2 receptors are the key residues, which have strong interactions with the active D1/D2 compounds and may influence their functional profiles.