Fentanyl-Rewired: A 2‑Azaspiro[3.3]heptane Core Preserves μ‑Opioid Function

Fentanyl is a benchmark μ-opioid analgesic but is constrained by respiratory risk. Searching for new entities with reduced respiratory liability, pharmacophore portability was probed by replacing the piperidine moiety with 2-azaspiro[3.3]-heptane while preserving phenethyl/anilide geometry. This spiro analogue retained fentanyl-class behaviorμ-opioid receptor (MOR)-preferred binding (MOR > κ-opioid receptor (KOR) ≫ δ-opioid receptor (DOR)), absent β-arrestin-2 recruitment, and full hot-plate/tail-flick antinociceptiondespite ∼10²-fold right-shift in potency versus fentanyl. In mice, it was stable and short-acting with a serum half-life of ∼27 min after an intravenous bolus dose. Whole-body plethysmography showed rapid, dose-dependent depression of respiration that was evident only at high doses. In sum, these studies present a topology-level core swap; preserving the fentanyl signature while decoupling potency from exposure, mapping the pharmacophore's boundary conditions and providing an actionable, spiro-enabled blueprint to tune MOR signaling and dispositionand recover affinity via structure-activity relationship (SAR)for next-generation opioid leads.