Rapid Synthesis of Boc-2',6'-dimethyl-l-tyrosine and Derivatives and Incorporation into Opioid Peptidomimetics.

doi:10.1021/acsmedchemlett.5b00344

Paper

Rapid Synthesis of Boc-2',6'-dimethyl-l-tyrosine and Derivatives and Incorporation into Opioid Peptidomimetics.

Published Oct 21, 2015 · Aaron M. Bender, Nicholas W. Griggs, Chao Gao

ACS medicinal chemistry letters

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17

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0

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Abstract

The unnatural amino acid 2',6'-dimethyl-l-tyrosine has found widespread use in the development of synthetic opioid ligands. Opioids featuring this residue at the N-terminus often display superior potency at one or more of the opioid receptor types, but the availability of the compound is hampered by its cost and difficult synthesis. We report here a short, three-step synthesis of Boc-2',6'-dimethyl-l-tyrosine (3a) utilizing a microwave-assisted Negishi coupling for the key carbon-carbon bond forming step, and employ this chemistry for the expedient synthesis of other unnatural tyrosine derivatives. Three of these derivatives (3c, 3d, 3f) have not previously been examined as Tyr(1) replacements in opioid ligands. We describe the incorporation of these tyrosine derivatives in a series of opioid peptidomimetics employing our previously reported tetrahydroquinoline (THQ) scaffold, and the binding and relative efficacy of each of the analogues at the three opioid receptor subtypes: mu (MOR), delta (DOR), and kappa (KOR).

Study Snapshot

This study demonstrates a rapid synthesis of Boc-2',6'-dimethyl-l-tyrosine and its derivatives, which can be incorporated into opioid peptidomimetics for improved potency at mu, delta, and kappa receptors.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Rapid Synthesis of Boc-2',6'-dimethyl-l-tyrosine and Derivatives and Incorporation into Opioid Peptidomimetics.

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References

Citations

Unnatural Amino Acids: Strategies, Designs, and Applications in Medicinal Chemistry and Drug Discovery.

Unnatural amino acids (UAAs) are critical tools in peptide- and peptidomimetic-based drugs, optimizing physicochemical parameters and improving target selectivity.

Recent developments in the chemistry of Negishi coupling: a review

Negishi coupling has been used to synthesize various natural products and biologically active compounds, aiding in the development of mild and sustainable strategies for pharmaceutical scaffolds.

(L)-Monomethyl Tyrosine (Mmt): New Synthetic Strategy via Bulky ‘Forced-Traceless’ Regioselective Pd-Catalyzed C(sp2)–H Activation

This study presents a new synthetic strategy for obtaining (L)-monomethyl tyrosine (Mmt) using Pd-catalyzed ortho-C(sp2)-H activation, enabling its use in opioid peptide chains with improved bioactivity and pharmacological profile.

Facile Functionalization of Ambipolar, Nitrogen-Doped PAHs toward Highly Efficient TADF OLED Emitters

This study developed a novel design of nitrogen-doped polycyclic aromatic hydrocarbons (PAHs) for efficient thermally activated delayed fluorescence (TADF) emitters, resulting in excellent photoluminescence quantum yield and high luminance values in organic light-emitting diodes.

Synthesis of 2,6-Dimethyltyrosine-Like Amino Acids through Pinacolinamide-Enabled C-H Dimethylation of 4-Dibenzylamino Phenylalanine.

This study demonstrates the synthesis of 2,6-dimethyltyrosine-like amino acids using pinacolinamide-enabled C-H dimethylation of 4-dibenzylamino phenylalanine, enabling diverse electronic and steric properties.