Role of 2',6'-dimethyl-l-tyrosine (Dmt) in some opioid lead compounds.

Abstract

Here we evaluated how the interchange of the amino acids 2',6'-dimethyl-L-tyrosine (Dmt), 2',6'-difluoro-L-tyrosine (Dft), and tyrosine in position 1 can affect the pharmacological characterization of some reference opioid peptides and pseudopeptides. Generally, Dft and Tyr provide analogues with a similar pharmacological profile, despite different pK(a) values. Dmt/Tyr(Dft) replacement gives activity changes depending on the reference opioid in which the modification was made. Whereas, H-Dmt-Tic-Asp *-Bid is a potent and selective delta agonist (MVD, IC(50)=0.12nM); H-Dft-Tic-Asp *-Bid and H-Tyr-Tic-Asp *-Bid are potent and selective delta antagonists (pA(2)=8.95 and 8.85, respectively). When these amino acids are employed in the synthesis of deltorphin B and its Dmt(1) and Dft(1) analogues, the three compounds maintain a very similar delta agonism (MVD, IC(50) 0.32-0.53 nM) with a decrease in selectivity relative to the Dmt(1) analogue. In the less selective H-Dmt-Tic-Gly *-Bid the replacement of Dmt with Dft and Tyr retains the delta agonism but with a decrease in potency. Antagonists containing the Dmt-Tic pharmacophore do not support the exchange of Dmt with Dft or Tyr.

• Authors: Gianfranco Balboni, Erika Marzola, Yusuke Sasaki, Akihiro Ambo, Ewa D Marczak, Lawrence H Lazarus, Severo Salvadori
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 18 Issue 16 Pg. 6024-30 (Aug 15 2010) ISSN: 1464-3391 [Electronic] England
• PMID: 20637637 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Analgesics, Opioid
• Narcotic Antagonists
• Opioid Peptides
• Receptors, Opioid
• Receptors, Opioid, delta
• 2',6'-dimethyltyrosine
• 3,5-difluorotyrosine
• Tyrosine

Topics

• Analgesics, Opioid (chemistry, pharmacology)
• Animals
• Guinea Pigs
• Male
• Narcotic Antagonists
• Opioid Peptides (chemistry, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Opioid (agonists, metabolism)
• Receptors, Opioid, delta (agonists, antagonists & inhibitors, metabolism)
• Tyrosine (analogs & derivatives, chemistry, pharmacology)