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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


10


9

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

Authors

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

Abstract

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.