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

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.