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 pKa 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 δ agonist (MVD, IC50 = 0.12 nM); H-Dft-Tic-Asp∗-Bid and H-Tyr-Tic-Asp∗-Bid are potent and selective δ antagonists (pA2 = 8.95 and 8.85, respectively). When these amino acids are employed in the synthesis of deltorphin B and its Dmt1 and Dft1 analogues, the three compounds maintain a very similar δ agonism (MVD, IC50 0.32–0.53 nM) with a decrease in selectivity relative to the Dmt1 analogue. In the less selective H-Dmt-Tic-Gly∗-Bid the replacement of Dmt with Dft and Tyr retains the δ agonism but with a decrease in potency. Antagonists containing the Dmt-Tic pharmacophore do not support the exchange of Dmt with Dft or Tyr.
Role of 2′,6′-dimethyl-l-tyrosine (Dmt) in some opioid lead compounds
MARZOLA, Erika;SALVADORI, Severo
2010
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 pKa 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 δ agonist (MVD, IC50 = 0.12 nM); H-Dft-Tic-Asp∗-Bid and H-Tyr-Tic-Asp∗-Bid are potent and selective δ antagonists (pA2 = 8.95 and 8.85, respectively). When these amino acids are employed in the synthesis of deltorphin B and its Dmt1 and Dft1 analogues, the three compounds maintain a very similar δ agonism (MVD, IC50 0.32–0.53 nM) with a decrease in selectivity relative to the Dmt1 analogue. In the less selective H-Dmt-Tic-Gly∗-Bid the replacement of Dmt with Dft and Tyr retains the δ agonism but with a decrease in potency. Antagonists containing the Dmt-Tic pharmacophore do not support the exchange of Dmt with Dft or Tyr.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.