Fluoroalkoxylated C-3 and C-9 (S)-12-bromostepholidine analogues with D1R antagonist activity

• Published in: Bioorganic chemistry 2023-12, Vol.141, p.106862-106862, Article 106862
• Main Authors: Namballa, Hari K., Decker, Ann M., Dorogan, Michael, Gudipally, Ashok, Goclon, Jakub, Harding, Wayne W.
• Format: Article
• Language: English
• Subjects: beta-Arrestins; D1R; Dopamine; Receptors, Dopamine - metabolism; Stepholidine; Tetrahydroprotoberberine; THPB; β-Arrestin
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106862

[Display omitted] •C-3 and C-9 fluoroalkoxylated analogues of (S)-12-bromo-stepholidine were prepared.•The analogues were assayed for D1R activity in functional assays.•Compound 13a was found to be a new D1R antagonist in both cAMP-based and β-arrestin-based assays.•Compound 13a is selective for D1R over other dopamine receptors. To illuminate the tolerance of fluoroalkoxylated groups at the C-3 and C-9 positions of tetrahydroprotoberberines (THPBs) on D1R activity, C-3 and C-9 fluoroalkoxylated analogues of (S)-12-bromostepholidine were prepared and evaluated. All compounds examined were D1R antagonists as measured by a cAMP assay. Our structure–activity studies herein indicate that the C-3 position tolerates a 1,1-difluoroethoxy substituent for D1R antagonist activity. Compound 13a was the most potent cAMP-based D1R antagonist identified and was also found to antagonize β-arrestin translocation in a TANGO assay. Affinity assessments at other dopamine receptors revealed that 13a is selective for D1R and unlike other naturally-occurring THPBs such as (S)-stepholidine, lacks D2R affinity. In preliminary biopharmaceutical assays, excellent BBB permeation was observed for 13a. Further pharmacological studies are warranted on (S)-stepholidine congeners to harvest their potential as a source of novel, druggable D1R-targeted agents.