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. 2018 Jul 18;9(7):1735-1742.
doi: 10.1021/acschemneuro.8b00085. Epub 2018 Apr 19.

Tyr1-ψ[( Z)CF═CH]-Gly2 Fluorinated Peptidomimetic Improves Distribution and Metabolism Properties of Leu-Enkephalin

Ryan A Altman  1 , Krishna K Sharma  1 , Lian G Rajewski  2 , Paul C Toren  2 , Michael J Baltezor  2 , Mohan Pal  3 , Somnath N Karad  4
Affiliations

Tyr1-ψ[( Z)CF═CH]-Gly2 Fluorinated Peptidomimetic Improves Distribution and Metabolism Properties of Leu-Enkephalin

Ryan A Altman et al. ACS Chem Neurosci. .

Abstract

Opioid peptides are key regulators in cellular and intercellular physiological responses, and could be therapeutically useful for modulating several pathological conditions. Unfortunately, the use of peptide-based agonists to target centrally located opioid receptors is limited by poor physicochemical (PC), distribution, metabolic, and pharmacokinetic (DMPK) properties that restrict penetration across the blood-brain barrier via passive diffusion. To address these problems, the present paper exploits fluorinated peptidomimetics to simultaneously modify PC and DMPK properties, thus facilitating entry into the central nervous system. As an initial example, the present paper exploited the Tyr1-ψ[( Z)CF═CH]-Gly2 peptidomimetic to improve PC druglike characteristics (computational), plasma and microsomal degradation, and systemic and CNS distribution of Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu). Thus, the fluoroalkene replacement transformed an instable in vitro tool compound into a stable and centrally distributed in vivo probe. In contrast, the Tyr1-ψ[CF3CH2-NH]-Gly2 peptidomimetic decreased stability by accelerating proteolysis at the Gly3-Phe4 position.

Keywords: Leu-enkephalin; Opioid peptides; fluorination; peptide CNS-distribution; peptide stability; peptidomimetics.

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Conflict of interest statement

Notes

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1. Hypothesis: FPMs Should Stabilize and Increase Distribution of Leu-Enkephalin
(HAC = Heavy Atom Count, HBD = Hydrogen-Bond Donors, HBA = Hydrogen-Bond Acceptors, TPSA = Topological Polar Surface Area, ACE = Angiotensin Converting Enzyme, AP-N = Aminopeptidase N)
Figure 2
Figure 2. Tyr1-ψ[(Z)CF=CH]-Gly2 Substitution Improves Plasma Stability of Leu-Enkephalin
( formula image) = Tyr1-ψ[(Z)CF=CH]-Gly2-Leu-Enkephalin ( formula image) = Leu-Enkephalin
Figure 3
Figure 3. Tyr1-ψ[(Z)CF=CH]-Gly2 Substitution Improves Microsomal Stability
( formula image) = Tyr1-ψ[(Z)CF=CH]-Gly2-Leu-Enkephalin, ( formula image) = Leu-Enkephalin, (▲) = Diphenhydramine (Mouse and Rat) or Verapamil (Human).
Figure 4
Figure 4. Tyr1-ψ[CF3CH2–NH]-Gly2 Substitution Worsens Plasma and Microsomal Stability
( formula image) = Leu-Enkephalin (1), ( formula image) = Tyr1-ψ[(R)-CF3CH2–NH]-Gly2-Leu-enkephalin (3), ( formula image) = Tyr1-ψ[(S)-CF3CH2–NH]-Gly2-Leu-enkephalin (4), (●) = Diphenhydramine
Figure 5
Figure 5. Tyr1-ψ[(Z)CF=CH]-Gly2-Leu-Enkephalin Is Orally Available and Distributes into the CNS
( formula image) = IV 50 mg/kg Tyr1-ψ[(Z)CF=CH]-Gly2-Leu-Enkephalin, ( formula image) = PO 400 mg/kg Tyr1-ψ[(Z)CF=CH]-Gly2-Leu-Enkephalin
See this image and copyright information in PMC

References

    1. Vallejo R, Barkin RL, Wang VC. Pharmacology of opioids in the treatment of chronic pain syndromes. Pain Physician. 2011;14:E343–E360. - PubMed
    1. Gentilucci L, Tolomelli A, Squassabia F. Peptides and peptidomimetics in medicine, surgery and biotechnology. Curr Med Chem. 2006;13:2449–2466. - PubMed
    1. Yeomans MR, Gray RW. Opioid peptides and the control of human ingestive behaviour. Neurosci Biobehav Rev. 2002;26:713–728. - PubMed
    1. Witt KA, Davis TP. CNS drug delivery: Opioid peptides and the blood-brain barrier. AAPS J. 2006;8:E76–E88. - PMC - PubMed
    1. Cornford EM, Braun LD, Crane PD, Oldendorf WH. Blood-brain barrier restriction of peptides and the low uptake of enkephalins. Endocrinology. 1978;103:1297–1303. - PubMed

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