24. Synthesis and Opioid Activity of Tyr1–ψ[(Z)CF=CH]–Gly2 and Tyr1–ψ[(S)/(R)-CF3CH–NH]–Gly2 Leu-enkephalin Fluorinated Peptidomimetics

Karad, S. N.; Pal, M.; Crowley, R. S.; Prisinzano, T. E.; Altman, R. A.*

ChemMedChem 2017, 12, 571–576.

We describe the design, synthesis, and opioid activity of fluoroalkene (Tyr1-ψ[(Z)CF=CH]-Gly2) and trifluoroethylamine (Tyr1-ψ[(S)/(R)-CF3CH-NH]-Gly2) analogues of the endogenous opioid neuropeptide, Leu-enkephalin. The fluoroalkene peptidomimetic exhibited low nanomolar functional activity (5.0±2 nm and 60±15 nm for δ- and μ-opioid receptors, respectively) with a μ/δ-selectivity ratio that mimics that of the natural peptide. However, the trifluoroethylamine peptidomimetics, irrespective of stereochemistry, did not activate the opioid receptors, which suggest that bulky CF3 substituents are not tolerated at this position.