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

Somnath Narayan Karad; Mohan Pal; Rachel S. Crowley; Thomas E. Prisinzano; Ryan A. Altman

doi:10.1002/cmdc.201700103

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

Somnath Narayan Karad, Mohan Pal, Rachel S. Crowley, Thomas E. Prisinzano, Ryan A. Altman

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	571-576
Number of pages	6
Journal	ChemMedChem
Volume	12
Issue number	8
DOIs	https://doi.org/10.1002/cmdc.201700103
State	Published - Apr 20 2017

Bibliographical note

Funding Information:
Research reported in this publication was supported by the US National Institute on Drug Abuse under Award Numbers DA036730 (R.A.A.) and DA018151 (T.E.P.), and by the US National Institute of General Medical Sciences under Award Number GM008545 (R.S.C.). Support for the NMR instrumentation was provided by NIH Shared Instrumentation Grant no. S10D016360. We thank Ben Neuenswander for HPLC purifications, and Dr. Victor Day for X-ray crystallography. The content herein is the sole responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health.

Publisher Copyright:
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Keywords

amide bonds
enkephalin
fluorine
opioids
peptidomimetics

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Pharmacology
Drug Discovery
Pharmacology, Toxicology and Pharmaceutics (all)
Organic Chemistry

Access to Document

10.1002/cmdc.201700103

Cite this

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

abstract = "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.",

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note = "Funding Information: Research reported in this publication was supported by the US National Institute on Drug Abuse under Award Numbers DA036730 (R.A.A.) and DA018151 (T.E.P.), and by the US National Institute of General Medical Sciences under Award Number GM008545 (R.S.C.). Support for the NMR instrumentation was provided by NIH Shared Instrumentation Grant no. S10D016360. We thank Ben Neuenswander for HPLC purifications, and Dr. Victor Day for X-ray crystallography. The content herein is the sole responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health. Publisher Copyright: {\textcopyright} 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim",

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AU - Prisinzano, Thomas E.

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