Abstract
The synthesis and biological evaluation of hybrid opioids consisting of Naloxone or Naltrexone and a partial opioid peptide are described. These compounds were synthesized in a homogeneous solution as well as in solid phase. A hydrazone linkage was employed to connect the alkaloids to the tetrapeptides. In synthesizing the peptides some non-traditional methods, which provided excellent results, were explored. The solid phase synthesis was achieved by anchoring the Fmoc-Phe to the 2-chlorotrityl resin, followed by stepwise addition of two Fmoc-Gly units. Each addition step preceded by standard piperidine removal of the Fmoc from the prior amino acid (AA) residue. The final AA, Tyr, was added as its Boc derivative. The Boc-tetrapeptide was then separated from the resin with a TFE/AcOH/CH2Cl2 mixture. In the solution synthesis, each peptide elongation step was accomplished by one-pot removal of the Fmoc from the prior AA residue and addition of the next Fmoc-AA. TBAF-thiol was used to cleanly remove the Fmoc, before adding the next Fmoc-AA in the presence of DIPEA and TBTU. All prepared hybrid ligands exhibited high affinities toward all three opioid receptors; moderate preferences for κ and μ receptors over δ receptor were observed. [35S]GTPγS binding assays indicated that these hybrid opioids are δ and μ antagonists but partial κ agonist.
Keywords: Hybrid opiates, Hybrid opioids, kappa agonist, naloxone derivative, naltrexone derivative, opiate agonist/ antagonist, peptide synthesis, Boc-tetrapeptide, DIPEA, TBTU
Medicinal Chemistry
Title:Synthesis and Biological Evaluation of Naloxone and Naltrexone-Derived Hybrid Opioids
Volume: 8 Issue: 4
Author(s): Bahman E. Nassim and Ming-Lei Wang
Affiliation:
Keywords: Hybrid opiates, Hybrid opioids, kappa agonist, naloxone derivative, naltrexone derivative, opiate agonist/ antagonist, peptide synthesis, Boc-tetrapeptide, DIPEA, TBTU
Abstract: The synthesis and biological evaluation of hybrid opioids consisting of Naloxone or Naltrexone and a partial opioid peptide are described. These compounds were synthesized in a homogeneous solution as well as in solid phase. A hydrazone linkage was employed to connect the alkaloids to the tetrapeptides. In synthesizing the peptides some non-traditional methods, which provided excellent results, were explored. The solid phase synthesis was achieved by anchoring the Fmoc-Phe to the 2-chlorotrityl resin, followed by stepwise addition of two Fmoc-Gly units. Each addition step preceded by standard piperidine removal of the Fmoc from the prior amino acid (AA) residue. The final AA, Tyr, was added as its Boc derivative. The Boc-tetrapeptide was then separated from the resin with a TFE/AcOH/CH2Cl2 mixture. In the solution synthesis, each peptide elongation step was accomplished by one-pot removal of the Fmoc from the prior AA residue and addition of the next Fmoc-AA. TBAF-thiol was used to cleanly remove the Fmoc, before adding the next Fmoc-AA in the presence of DIPEA and TBTU. All prepared hybrid ligands exhibited high affinities toward all three opioid receptors; moderate preferences for κ and μ receptors over δ receptor were observed. [35S]GTPγS binding assays indicated that these hybrid opioids are δ and μ antagonists but partial κ agonist.
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Cite this article as:
E. Nassim Bahman and Wang Ming-Lei, Synthesis and Biological Evaluation of Naloxone and Naltrexone-Derived Hybrid Opioids, Medicinal Chemistry 2012; 8 (4) . https://dx.doi.org/10.2174/157340612801216193
DOI https://dx.doi.org/10.2174/157340612801216193 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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