Endogenous opioid peptides regulate activity within the central nervous system (CNS), and are particularly interesting for treating pain, depression, and anxiety. Unfortunately, clinical use of peptide-based agents is restricted by poor physicochemical and biophysical properties, which limit penetration into the CNS. Therefore, many peptide-based probes cannot be employed clinically for treating many disease states. To address this problem, the we explore the use of fluorinated peptidomimetics (FPMs) to improve the drug-like properties of peptides, and to deliver peptides into the CNS. In this area, ongoing efforts involve the synthesis and characterization of rationally designed FPM- analogs of opioid peptides. In this presentation, we describe the design, synthesis, opioid activity, and stability 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, with a μ/δ-selectivity ratio that mimics that of the natural peptide, as well as improved stability and drug-like characteristics relative to the parent. However, the trifluoroethylamine peptidomimetics, irrespective of stereochemistry, did not activate the opioid receptors, and were unexpectedly rapidly metabolized in plasma. Thus, the fluoroalkene peptidomimetic serves as the new lead for future studies to improve (a) opioid potency, selectivity and signaling bias, and (b) physicochemical and biophysical drug-like characteristics. This overarching strategy should be amenable for modulating physicochemical and biophysical properties of a broad spectrum of neuropeptides, with the ultimate goal of providing a general strategy for converting small peptide-based in vitro tool compounds into in vivo CNS-active probes.

Fluorinated peptidomimetics for improving drug-like characteristics of opioid peptides

256th National Meeting (2018)

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