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Synthesis and Opioid Activity of Tyr1 -?[(Z)CF=CH]-Gly2 and Tyr1 -?[(S)/(R)-CF3 CH-NH]-Gly2 Leu-enkephalin Fluorinated Peptidomimetics.

ABSTRACT: We describe the design, synthesis, and opioid activity of fluoroalkene (Tyr1 -?[(Z)CF=CH]-Gly2 ) and trifluoroethylamine (Tyr1 -?[(S)/(R)-CF3 CH-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 ?- and ?-opioid receptors, respectively) with a ?/?-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.

SUBMITTER: Karad SN 

PROVIDER: S-EPMC5486982 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Karad Somnath Narayan SN   Pal Mohan M   Crowley Rachel S RS   Prisinzano Thomas E TE   Altman Ryan A RA  

ChemMedChem 20170405 8

We describe the design, synthesis, and opioid activity of fluoroalkene (Tyr<sup>1</sup> -ψ[(Z)CF=CH]-Gly<sup>2</sup> ) and trifluoroethylamine (Tyr<sup>1</sup> -ψ[(S)/(R)-CF<sub>3</sub> CH-NH]-Gly<sup>2</sup> ) 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, t  ...[more]

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