Synthesis and Opioid Activity of Tyr(1) -ψ[(Z)CF=CH]-Gly(2) and Tyr(1) -ψ[(S)/(R)-CF(3) CH-NH]-Gly(2) Leu-enkephalin Fluorinated Peptidomimetics

We describe the design, synthesis, and opioid activity of fluoroalkene (Tyr(1) -ψ[(Z)CF=CH]-Gly(2) ) and trifluoroethylamine (Tyr(1) -ψ[(S)/(R)-CF(3) CH-NH]-Gly(2) ) 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 CF(3) substituents are not tolerated at this position.