Synthesis and Biological Evaluation of Fentanyl Analogues Modified at Phenyl Groups with Alkyls

A series of fentanyl analogues modified at the phenyl group of the phenethyl with alkyl and/or hydroxyl and alkoxy, and the phenyl group in the anilido moiety replaced with benzyl or substituted benzyl, were synthesized. The in vitro opioid receptor functional activity of these compounds was evaluated by assessment of their ability to modulate forskolin-stimulated cAMP accumulation and by their ability to induce beta-arrestin2 recruitment. Compound 12 is a potent mu-opioid (MOP) receptor agonist, a potent kappa-opioid (KOP) receptor antagonist with weak beta-arrestin2 recruitment activity. Compounds 10 and 11 are potent MOP receptor agonists with weak delta-opioid (DOP) receptor antagonist activity and moderate KOP receptor antagonist activity as well as weak beta-arrestin2 recruitment activity at the MOP receptor. These compounds are promising leads for discovery of potent opioid analgesics with reduced side effects relative to clinically available strong opioid analgesics.