Assessment of the antinociceptive, respiratory-depressant, and reinforcing effects of low pKa fluorinated fentanyl analogs FF3 and NFEPP

Low pKa fluorinated fentanyl analogs (FF3 and NFEPP) are tested for how well they separate pain relief from typical opioid harms such as respiratory depression and reinforcement. In male and female Sprague-Dawley rats, the study compares inflammatory antinociception (using a Von Frey test), respiratory depression (whole-body plethysmography), and drug reinforcing effects (self-administration with a progressive-ratio schedule) after dosing fentanyl, FF3, and NFEPP over ranges spanning no effect to maximal effects. FF3 and fentanyl produced similar potency and efficacy for antinociception and reinforcing effects, while FF3 showed lower potency than fentanyl for respiratory depression. NFEPP was less potent than fentanyl across every measure, suggesting a larger potency gap between analgesia and other opioid-typical effects for FF3, with different tradeoffs for NFEPP. The work supports the idea that lowering fentanyl analog pKa might improve the safety profile as analgesics, but it also notes that additional study is needed to determine the optimal pKa difference.