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Papers of the Week

Papers: 14 Sep 2019 - 20 Sep 2019

Pharmacology/Drug Development

2019 Sep 12

ACS Med Chem Lett



β-Fluorofentanyls Are pH-Sensitive Mu Opioid Receptor Agonists.


Rosas R, Huang X-P, Roth BL, Dockendorff C
ACS Med Chem Lett. 2019 Sep 12; 10(9):1353-1356.
PMID: 31531209.


The concept recently postulated by Stein and co-workers (, , 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 (IC) 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.