β-Fluorofentanyls Are pH-Sensitive Mu Opioid Receptor Agonists

Authors

Ricardo Rosas Jr., Marquette University
Xi-Ping Huang, University of North Carolina - Chapel Hill
Bryan L. Roth, University of North Carolina - Chapel Hill
Chris Dockendorff, Marquette UniversityFollow

Document Type

Article

Language

eng

Publication Date

8-13-2019

Publisher

American Chemical Society Publications

Source Publication

ACS Medicinal Chemistry Letters

Source ISSN

1948-5875

Abstract

The concept recently postulated by Stein and co-workers (Science2017, 355, 966) that mu opioid receptor (MOR) agonists possessing amines with attenuated basicity show pH-dependent activity and can selectively act at damaged, low pH tissues has been additionally supported by in vitro studies reported here. We synthesized and tested analogs of fentanyl possessing one or two fluorine atoms at the beta position of the phenethylamine side chain, with additional fluorines optionally added to the benzene ring of the side chain. These compounds were synthesized in 1 to 3 steps from commercial building blocks. The novel bis-fluorinated analog RR-49 showed superior pH sensitivity, with full efficacy relative to DAMGO, but with 19-fold higher potency (IC₅₀) in a MOR cAMP assay at pH 6.5 versus 7.4. Such compounds hold significant promise as analgesics for inflammatory pain with reduced abuse potential.

Comments

ACS Medicinal Chemistry Letters, Vol. 10, No. 9 (August 13, 2019): 1353-1356. DOI. © 2019 American Chemical Society Publication. Used with permission.

Recommended Citation

Rosas, Ricardo Jr.; Huang, Xi-Ping; Roth, Bryan L.; and Dockendorff, Chris, "β-Fluorofentanyls Are pH-Sensitive Mu Opioid Receptor Agonists" (2019). Chemistry Faculty Research and Publications. 990.
https://epublications.marquette.edu/chem_fac/990