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

BALBONI, GIANFRANCO;MARZOLA E;SASAKI Y;AMBO A;MARCZAK E. D;LAZARUS L. H;SALVADORI S.

2010-01-01

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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.