ml9b00335_si_001.pdf (4.27 MB)
β‑Fluorofentanyls Are pH-Sensitive Mu Opioid Receptor Agonists
journal contribution
posted on 2019-08-15, 16:34 authored by Ricardo Rosas, Xi-Ping Huang, Bryan L. Roth, Chris DockendorffThe concept recently postulated by
Stein and co-workers (Science 2017, 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.
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benzene ringcompoundphenethylamine side chainmu opioid receptorattenuated basicity show pH-dependent activityside chainbuilding blocksDAMGOfluorines optionallypH sensitivitynovel bis-fluorinated analog RR -49beta positionScience 20173 stepsMOR cAMP assayIC 50fluorine atomspH-Sensitive Mu Opioid Receptor AgonistspH 6.5pH tissues
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