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

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

  • Bioorg Chem. 2023 Dec:141:106862. doi: 10.1016/j.bioorg.2023.106862.
Hari K Namballa 1,  Ann M Decker 2,  Michael Dorogan 1,  Ashok Gudipally 3,  Jakub Goclon 1,  Wayne W Harding 4
Affiliations

Affiliations

  • 1 Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, United States.
  • 2 Center for Drug Discovery, RTI International, Research Triangle Park, NC 27709, United States.
  • 3 Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, United States; Program in Chemistry, CUNY Graduate Center 365 5th Avenue, New York, NY 10016, United States.
  • 4 Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, United States; Program in Chemistry, CUNY Graduate Center 365 5th Avenue, New York, NY 10016, United States; Program in Biochemistry, CUNY Graduate Center 365 5th Avenue, New York, NY 10016, United States. Electronic address: wayne.harding@hunter.cuny.edu.
PMID: 37722267 DOI: 10.1016/j.bioorg.2023.106862
Abstract

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.

Keywords

D1R; Dopamine; Stepholidine; THPB; Tetrahydroprotoberberine; β-Arrestin.

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